Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use

ABSTRACT

In its many embodiments, the present invention provides certain iminothiadiazine dioxide compounds, including compounds Formula (I): (I) and include stereoisomers thereof, and pharmaceutically acceptable salts of said compounds stereoisomers, wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , R 9 , ring A, ring B, m, n, p, -L 1 -, L 2 -, and L 3 - is selected independently and as defined herein. The novel iminothiadiazine dioxide compounds of the invention have surprisingly been found to exhibit properties which are expected to render them advantageous as BACE inhibitors and/or for the treatment and prevention of various pathologies related to β-amyloid (Aβ) production. Pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other active agents), and methods for their preparation and use in treating pathologies associated with amyloid beta (Aβ) protein, including Alzheimers disease, are also disclosed.

RELATED APPLICATIONS

This application claims priority to provisional application U.S. Ser.No. 61/249,685, filed Oct. 8, 2009, incorporated herein by reference.

FIELD OF THE INVENTION

This invention provides certain iminothiadiazine dioxide compounds andcompositions comprising these compounds. The novel iminothiadiazinedioxide compounds of the invention have surprisingly been found toexhibit properties which are expected to render them advantageous asBACE inhibitors and/or for the treatment and prevention of variouspathologies related to β-amyloid (“Aβ”) production.

BACKGROUND

Amyloid beta peptide (“Aβ”) is a primary component of β amyloid fibrilsand plaques, which are regarded as having a role in an increasing numberof pathologies. Examples of such pathologies include, but are notlimited to, Alzheimer's disease, Down's syndrome, Parkinson's disease,memory loss (including memory loss associated with Alzheimer's diseaseand Parkinson's disease), attention deficit symptoms (includingattention deficit symptoms associated with Alzheimer's disease (“AD”),Parkinson's disease, and Down's syndrome), dementia (includingpre-senile dementia, senile dementia, dementia associated withAlzheimer's disease, Parkinson's disease, and Down's syndrome),progressive supranuclear palsy, cortical basal degeneration,neurodegeneration, olfactory impairment (including olfactory impairmentassociated with Alzheimer's disease, Parkinson's disease, and Down'ssyndrome), β-amyloid angiopathy (including cerebral amyloid angiopathy),hereditary cerebral hemorrhage, mild cognitive impairment (“MCI”),glaucoma, amyloidosis, type II diabetes, hemodialysis (β2 microglobulinsand complications arising therefrom), neurodegenerative diseases such asscrapie, bovine spongiform encephalitis, Creutzfeld-Jakob disease,traumatic brain injury and the like.

Aβ peptides are short peptides which are made from the proteolyticbreak-down of the transmembrane protein called amyloid precursor protein(“APP”). Aβ peptides are made from the cleavage of APP by β-secretaseactivity near the position near the N-terminus of Aβ, and bygamma-secretase activity at a position near the C-terminus of Aβ. (APPis also cleaved by α-secretase activity, resulting in the secreted,non-amyloidogenic fragment known as soluble APPα.) Beta site APPCleaving Enzyme (“BACE-1”) is regarded as the primary aspartyl proteaseresponsible for the production of Aβ by β-secretase activity. Theinhibition of BACE-1 has been shown to inhibit the production of Aβ.

AD is estimated to afflict more than 20 million people worldwide and isbelieved to be the most common cause of dementia. AD is a diseasecharacterized by degeneration and loss of neurons and also by theformation of senile plaques and neurofibrillary tangles. Presently,treatment of Alzheimer's disease is limited to the treatment of itssymptoms rather than the underlying causes. Symptom-improving agentsapproved for this purpose include, for example, N-methyl-D-aspartatereceptor antagonists such as memantine (Namenda®, ForrestPharmaceuticals, Inc.), cholinesterase inhibitors such as donepezil(Aricept®, Pfizer), rivastigmine (Exelon®, Novartis), galantamine(Razadyne Reminyl®), and tacrine (Cognex®).

In AD, Aβ peptides, formed through β-secretase and gamma-secretaseactivity, can form tertiary structures that aggregate to form amyloidfibrils. Aβ peptides have also been shown to form Aβ oligomers(sometimes referred to as “Aβ aggregates” or “Abeta oligomers”). Aβoligomers are small multimeric structures composed of 2 to 12 Aβpeptides that are structurally distinct from Ag fibrils. Amyloid fibrilscan deposit outside neurons in dense formations known as senile plaques,neuritic plaques, or diffuse plaques in regions of the brain importantto memory and cognition. Aβ oligomers are cytotoxic when injected in thebrains of rats or in cell culture. This Aβ plaque formation anddeposition and/or Aβ oligomer formation, and the resultant neuronaldeath and cognitive impairment, are among the hallmarks of ADpathophysiology. Other hallmarks of AD pathophysiology includeintracellular neurofibrillary tangles comprised of abnormallyphosphorylated tau protein, and neuroinflammation.

Evidence suggests that Aβ, Aβ fibrils, aggregates, oligomers, and/orplaque play a causal role in AD pathophysiology. (Ohno et al.,Neurobiology of Disease, No. 26 (2007), 134-145). Mutations in the genesfor APP and presenilins 1/2 (PS1/2) are known to cause familial AD andan increase in the production of the 42-amino acid form of Aβ isregarded as causative. Aβ has been shown to be neurotoxic in culture andin vivo. For example, when injected into the brains of aged primates,fibrillar Aβ causes neuronal cell death around the injection site. Otherdirect and circumstantial evidence of the role of Aβ in Alzheimeretiology has also been published.

BACE-1 has become an accepted therapeutic target for the treatment ofAlzheimer's disease. For example, McConlogue et al., J. Bio. Chem., Vol.282, No. 36 (September 2007), have shown that partial reductions ofBACE-1 enzyme activity and concomitant reductions of Aβ levels lead to adramatic inhibition of Aβ-driven AD-like pathology, making f-secretase atarget for therapeutic intervention in AD. Ohno et al. Neurobiology ofDisease, No. 26 (2007), 134-145, report that genetic deletion of BACE-1in 5XFAD mice abrogates Aβ generation, blocks amyloid deposition,prevents neuron loss found in the cerebral cortex and subiculum (brainregions manifesting the most severe amyloidosis in 5XFAD mice), andrescues memory deficits in 5XFAD mice. The group also reports that Aβ isultimately responsible for neuron death in AD and concludes that BACE-1inhibition has been validated as an approach for the treatment of AD.Roberds et al., Human Mol. Genetics, 2001, Vol. 10, No. 12, 1317-1324,established that inhibition or loss of β-secretase activity produces noprofound phenotypic defects while inducing a concomitant reduction inAβ. Luo et al., Nature Neuroscience, Vol. 4, No. 3, March 2001, reportthat mice deficient in BACE-1 have normal phenotype and abolishedβ-amyloid generation.

BACE-1 has also been identified or implicated as a therapeutic targetfor a number of other diverse pathologies in which Aβ or Aβ fragmentshave been identified to play a causative role. One such example is inthe treatment of AD-type symptoms of patients with Down's syndrome. Thegene encoding APP is found on chromosome 21, which is also thechromosome found as an extra copy in Down's syndrome. Down's syndromepatients tend to acquire AD at an early age, with almost all those over40 years of age showing Alzheimer's-type pathology. This is thought tobe due to the extra copy of the APP gene found in these patients, whichleads to overexpression of APP and therefore to increased levels of Aβcausing the prevalence of AD seen in this population. Furthermore,Down's patients who have a duplication of a small region of chromosome21 that does not include the APP gene do not develop AD pathology. Thus,it is thought that inhibitors of BACE-1 could be useful in reducingAlzheimer's type pathology in Down's syndrome patients.

Another example is in the treatment of glaucoma (Guo et al., PNAS, Vol.104, No. 33, Aug. 14, 2007). Glaucoma is a retinal disease of the eyeand a major cause of irreversible blindness worldwide. Guo et al. reportthat Aβ colocalizes with apoptotic retinal ganglion cells (RGCs) inexperimental glaucoma and induces significant RGC cell loss in vivo in adose- and time-dependent manner. The group report having demonstratedthat targeting different components of the Aβ formation and aggregationpathway, including inhibition of β-secretase alone and together withother approaches, can effectively reduce glaucomatous RGC apoptosis invivo. Thus, the reduction of Aβ production by the inhibition of BACE-1could be useful, alone or in combination with other approaches, for thetreatment of glaucoma.

Another example is in the treatment of olfactory impairment. Getchell etal., Neurobiology of Aging, 24 (2003), 663-673, have observed that theolfactory epithelium, a neuroepithelium that lines the posterior-dorsalregion of the nasal cavity, exhibits many of the same pathologicalchanges found in the brains of AD patients, including deposits of Aβ,the presence of hyperphosphorylated tau protein, and dystrophic neuritesamong others. Other evidence in this connection has been reported byBacon A W, et al., Ann NY Acad Sci 2002; 855:723-31; Crino P B, Martin JA, Hill W D, et al., Ann Otol Rhinol Laryngol, 1995; 104:655-61; DaviesD C, et al., Neurobiol Aging, 1993; 14:353-7; Devanand D P, et al., Am JPsychiatr, 2000; 157:1399-405; and Doty R L, et al., Brain Res Bull,1987; 18:597-600. It is reasonable to suggest that addressing suchchanges by reduction of Aβ by inhibition of BACE-1 could help to restoreolfactory sensitivity in patients with AD.

For compounds which are inhibitors of BACE-2, another example is in thetreatment of type-II diabetes, including diabetes associated withamyloidogenesis. BACE-2 is expressed in the pancreas. BACE-2immunoreactivity has been reported in secretory granules of beta cells,co-stored with insulin and IAPP, but lacking in the other endocrine andexocrine cell types. Stoffel et al., WO2010/063718, disclose the use ofBACE-2 inhibitors in the treatment of metabolic diseases such as Type-IIdiabetes. The presence of BACE-2 in secretory granules of beta cellssuggests that it may play a role in diabetes-associated amyloidogenesis.(Finzi, G. Franzi, et al., Ultrastruct Pathol 2008 November-December;32(6):246-51.)

Other diverse pathologies characterized by the formation and depositionof Aβ or fragments thereof, and/or by the presence of amyloid fibrils,oligomers, and/or plaques, include neurodegenerative diseases such asscrapie, bovine spongiform encephalitis, traumatic brain injury (“TBI”),Creutzfeld-Jakob disease and the like, type II diabetes (which ischaracterized by the localized accumulation of cytotoxic amyloid fibrilsin the insulin producing cells of the pancreas), and amyloid angiopathy.In this regard reference can be made to the patent literature. Forexample, Kong et al., US2008/0015180, disclose methods and compositionsfor treating amyloidosis with agents that inhibit Aβ peptide formation.As another example, Loane, et al. report the targeting of amyloidprecursor protein secretases as therapeutic targets for traumatic braininjury. (Loane et al., “Amyloid precursor protein secretases astherapeutic targets for traumatic brain injury”, Nature Medicine,Advance Online Publication, published online Mar. 15, 2009.) Still otherdiverse pathologies characterized by the inappropriate formation anddeposition of Aβ or fragments thereof, and/or by the presence of amyloidfibrils, and/or for which inhibitor(s) of BACE-1 is expected to be oftherapeutic value are discussed further hereinbelow.

The therapeutic potential of inhibiting the deposition of Aβ hasmotivated many groups to characterize BACE-1 and to identify inhibitorsof BACE-1 and of other secretase enzyme inhibitors. Examples from thepatent literature are growing and include WO02006009653, WO2007005404,WO2007005366, WO2007038271, WO02007016012, US2005/0282826, US2007072925,WO2007149033, WO2007145568, WO2007145569, WO2007145570, WO2007145571,WO2007114771, US20070299087, WO2005/016876, WO2005/014540,WO2005/058311, WO2006/065277, WO2006/014762, WO2006/014944,WO2006/138195, WO2006/138264, WO2006/138192, WO2006/138217,WO2007/050721, WO2007/053506, WO2007/146225, WO2006/138230,WO2006/138265, WO2006/138266, WO2007/053506, WO2007/146225,WO2008/073365, WO2008/073370, WO2008/103351, US2009/041201,US2009/041202, and WO2010/047372.

SUMMARY OF THE INVENTION

The present invention provides certain iminothiadiazine dioxidecompounds which are collectively or individually referred to herein as“compound(s) of the invention”, as described herein. The noveliminothiadiazine dioxide compounds of the invention have surprisinglybeen found to exhibit properties which are expected to render themadvantageous as BACE inhibitors and/or for the treatment and preventionof the various pathologies described herein.

In each of the various embodiments of the compounds of the inventiondescribed herein, each variable including those of Formulas (I), (IA),(IA-1), (IA-2), (II), (IIA), (IIA-1), and (IIA-2), and the variousembodiments thereof, each variable is selected independently of theothers unless otherwise indicated.

In each of the various embodiments of the compounds of the inventiondescribed herein, including those of Formulas (I), (IA), (IA-1), (IA-2),(II), (IIA), (IIA-1), and (IIA-2), and the various embodiments thereofand the compounds of the examples, such formulas and examples areintended to encompass all forms of the compounds such as, for example,any solvates, hydrates, stereoisomers, and tautomers of said compoundsand of any pharmaceutically acceptable salts thereof.

In one embodiment, the compounds of the invention have the structuralFormula (I):

and include tautomers, solvates, prodrugs, and esters thereof, andpharmaceutically acceptable salts of said compounds, tautomers,solvates, prodrugs, and esters,

wherein:

-L₁- represents a bond or a divalent moiety selected from the groupconsisting of -alkyl-, -haloalkyl-, -heteroalkyl-, -alkenyl-, and-alkynyl-;

-L₂- represents a bond or a divalent moiety selected from the groupconsisting of -alkyl-, -haloalkyl-, -heteroalkyl-, -alkenyl-, and-alkynyl-;

each -L₃- independently represents a bond or a divalent moietyindependently selected from the group consisting of -alkyl-,-haloalkyl-, -heteroalkyl-, -alkenyl-, -alkynyl-, —N(R⁷)—, —NHC(O)—,—C(O)NH—, —NHS(O)₂—, —S(O)₂NH—, —O-alkyl-, -alkyl-O—, —N(R⁷)-alkyl-,-alkyl-N(R⁷)—, -haloalkyl-NH—, and —NH-haloalkyl-;

m, n, and p are each independently selected integers, wherein:

m is 0 or more;

n is 0 or more; and

p is 0 or more,

wherein the maximum value of the sum of m and n is the maximum number ofavailable substitutable hydrogen atoms on ring A, and wherein themaximum value of p is the maximum number of available substitutablehydrogen atoms on ring B;

R¹ is selected from the group consisting of: H, alkyl, haloalkyl,heteroalkyl, heterohaloalkyl, cycloalkyl, cycloalkylalkyl-,heterocycloalkyl, heterocycloalkylalkyl-, aryl, arylalkyl-, heteroaryl,and heteroarylalkyl-,

-   -   wherein each of said alkyl, haloalkyl, heteroalkyl,        heterohaloalkyl, cycloalkyl, cycloalkylalkyl-, heterocycloalkyl,        heterocycloalkylalkyl-, aryl, arylalkyl-, heteroaryl, and        heteroarylalkyl- of R¹ is unsubstituted or substituted with one        or more independently selected R¹⁰ groups;    -   R² is selected from the group consisting of H, halo, alkyl,        haloalkyl, and heteroalkyl, wherein each of said alkyl and said        haloalkyl of R² is unsubstituted or substituted with one or more        independently selected R¹⁰ groups;    -   R³ is selected from the group consisting of H, halo, alkyl,        haloalkyl, and heteroalkyl, wherein each of said alkyl and said        haloalkyl of R² is unsubstituted or substituted with one or more        independently selected R¹⁰ groups;

R⁴ is selected from the group consisting of alkyl, aryl, heteroaryl,cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl,

-   -   wherein each of said alkyl, aryl, heteroaryl, cycloalkyl,        cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl of R⁴ is        unsubstituted or substituted with one or more independently        selected R¹ groups;

ring A is selected from the group consisting of monocyclic aryl,monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl,monocyclic heterocycloalkyl, monocyclic heterocycloalkenyl, and amulticyclic group;

each ring B (when present) is independently selected from the groupconsisting of monocyclic aryl, monocyclic heteroaryl, monocycliccycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycloalkyl,monocyclic heterocycloalkenyl, and a multicyclic group;

each R⁵ (when present) is independently selected from the groupconsisting of halo, —CN, —SF₅, —OSF₅, —NO₂, —Si(R⁶)₃, —P(O)(OR⁷)₂,—P(O)(OR⁷)(R⁷), —N(R⁸)₂, —NR⁸C(O)R⁷, —NR⁸S(O)₂R⁷, —NR⁸C(O)N(R⁸)₂,—NR⁸C(O)OR⁷, —C(O)R⁷, —C(O)₂R⁷, —C(O)N(R⁸)₂, —S(O)R⁷, —S(O)₂R⁷,—S(O)₂N(R⁸)₂, —OR⁷, —SR⁷, alkyl, haloalkyl, haloalkoxy, heteroalkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,

-   -   wherein each said alkyl, haloalkyl, haloalkoxy, heteroalkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl of R⁵ (when present) is optionally independently        unsubstituted or further substituted with one or more        independently selected groups selected from the group consisting        of lower alkyl, lower alkenyl, lower alkynyl, lower heteroalkyl,        halo, —CN, —SF₅, —OSF₅, —NO₂, —N(R⁸)₂, —OR⁷, —C(O)N(R⁸)₂, and        cycloalkyl;

each R⁶ (when present) is independently selected from the groupconsisting of alkyl, aryl, arylalkyl-, haloalkyl, cycloalkyl,cycloalkylalkyl-, heteroaryl, and heteroarylalkyl-;

each R⁷ (when present) is independently selected from the groupconsisting of H, alkyl, alkenyl, heteroalkyl, haloalkyl, aryl,arylalkyl-, heteroaryl, heteroarylalkyl-, cycloalkyl, cycloalkylalkyl-,heterocycloalkyl, and heterocycloalkylalkyl-;

each R⁸ (when present) is independently selected from the groupconsisting of H, alkyl, alkenyl, heteroalkyl, haloalkyl, haloalkenyl,aryl, arylalkyl-, heteroaryl, heteroarylalkyl-, cycloalkyl,cycloalkylalkyl-, heterocycloalkyl, and heterocycloalkylalkyl-;

each R⁹ (when present) is independently selected from the groupconsisting of: halogen, —CN, —SF₅, —OSF₅, —NO₂, —Si(R⁶)₃, —P(O)(OR⁷)₂,—P(O)(OR)(R⁷), —N(R⁸)₂, —NR⁸C(O)R⁷, —NR⁸S(O)₂R⁷, —NR⁸C(O)N(R⁸)₂,—NR⁸C(O)OR⁷, —C(O)R⁷, —C(O)₂R⁷, —C(O)N(R⁸)₂, —S(O)R⁷, —S(O)₂R⁷,—S(O)₂N(R⁸)₂, —OR⁷, —SR⁷, alkyl, haloalkyl, heteroalkyl, alkenyl,alkynyl, aryl, arylalkyl-, cycloalkyl, heteroaryl, heteroarylalkyl-, andheterocycloalkyl;

each R¹⁰ (when present) is independently selected from the groupconsisting of halo, —CN, —NO₂, —Si(R⁶)₃, —P(O)(OR⁷)₂, —P(O)(OR)(R⁷),—N(R⁸)₂, —NR⁸C(O)R⁷, —NR⁸S(O)₂R⁷, —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)OR⁷, —C(O)R⁷,—C(O)₂R⁷, —C(O)N(R⁸)₂, —S(O)R⁷, —S(O)₂R⁷, —S(O)₂N(R⁸)₂, —OR⁷, —SR⁷,alkyl, haloalkyl, haloalkoxy, heteroalkyl, alkenyl, alkynyl, andcycloalkyl,

-   -   wherein each said alkyl, haloalkyl, haloalkoxy, heteroalkyl,        alkenyl, alkynyl, and cycloalkyl of R¹⁰ (when present) is        optionally independently unsubstituted or further substituted        with one or more independently selected groups selected from the        group consisting of lower alkyl, lower alkenyl, lower alkynyl,        lower heteroalkyl, halo, —CN, —NO₂, —N(R⁸)₂, —OR⁷, and        —C(O)N(R⁸)₂.

In other embodiments, the invention provides compositions, includingpharmaceutical compositions, comprising one or more compounds of theinvention (e.g., one compound of the invention), or a tautomer thereof,or a pharmaceutically acceptable salt or solvate of said compound(s)and/or said tautomer(s), optionally together with one or more additionaltherapeutic agents, optionally in an acceptable (e.g., pharmaceuticallyacceptable) carrier or diluent.

In other embodiments, the invention provides various methods oftreating, preventing, ameliorating, and/or delaying the onset of anamyloid β pathology (Aβ pathology) and/or a symptom or symptoms thereof,comprising administering a composition comprising an effective amount ofone or more compounds of the invention, or a tautomer thereof, orpharmaceutically acceptable salt or solvate of said compound(s) and/orsaid tautomer(s), to a patient in need thereof. Such methods optionallyadditionally comprise administering an effective amount of one or moreadditional therapeutic agents suitable for treating the patient beingtreated.

These and other embodiments of the invention, which are described indetail below or will become readily apparent to those of ordinary skillin the art, are included within the scope of the invention.

DETAILED DESCRIPTION

In one embodiment, the compounds of the invention have the structuralFormula (I) as described above.

In one embodiment, the compounds of the invention have the structuralFormula (IA):

and include tautomers, and prodrugs thereof, and pharmaceuticallyacceptable salts, and solvates of said compounds, tautomers, andprodrugs, wherein R¹, L₁, L₂, L₃, R², R³, R⁴, R⁵, R⁹, ring A, ring B, m,n, and p are each as defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (IA-1):

and include tautomers, and prodrugs thereof, and pharmaceuticallyacceptable salts, and solvates of said compounds, tautomers, andprodrugs, wherein R¹, L₁, L₂, L₃, R², R³, R⁴, R⁵, R⁹, ring A, ring B, m,n, and p are each as defined in Formula (T).

In one embodiment, the compounds of the invention have the structuralFormula (IA-2):

and include tautomers, and prodrugs thereof, and pharmaceuticallyacceptable salts, and solvates of said compounds, tautomers, andprodrugs, wherein R¹, L₁, L₂, L₃, R², R³, R⁴, R⁵, R⁹, ring A, ring B, m,n, and p are each as defined in Formula (I).

In one embodiment, in each of Formulas (I), (IA), (IA-1), and (IA-2), R¹is selected from the group consisting of H, lower alkyl, andcyclopropyl.

In one embodiment, in each of Formulas (I), (IA), (IA-1), and (IA-2), R¹is selected from the group consisting of H and methyl.

In one embodiment, in each of Formulas (I), (IA), (IA-1), and (IA-2), R¹is H.

In one embodiment, in each of Formulas (I), (IA), (IA-1), and (IA-2), R¹is methyl.

In one embodiment, in each of Formulas (I), (IA), (IA-1), and (IA-2), R²is H.

In one embodiment, in each of Formulas (I), (IA), (IA-1), and (IA-2):

R¹ is selected from the group consisting of H, lower alkyl, andcyclopropyl; and

R² is H.

In one embodiment, in each of Formulas (I), (IA), (IA-1), and (IA-2), R³is H and R² is H.

In one embodiment, in each of Formulas (I), (IA), (IA-1), and (IA-2), R³is selected from the group consisting H, alkyl, haloalkyl, andheteroalkyl.

In one embodiment, in each of Formulas (I), (IA), (IA-1), and (IA-2), R³is selected from the group consisting H, lower alkyl, halo lower alkyl,and lower alkyl ether.

In one embodiment, in each of Formulas (I), (IA), (IA-1), and (IA-2), R³is selected from the group consisting H, alkyl, haloalkyl, andheteroalkyl; and R² is H.

In one embodiment, in each of Formulas (I), (IA), (IA-1), and (IA-2), R³is selected from the group consisting H, lower alkyl, halo lower alkyl,and lower alkyl ether; and R² is H.

In one embodiment, in each of Formulas (I), (IA), (IA-1), and (IA-2),-L₂- is a bond and R⁴ is lower alkyl.

In one embodiment, in each of Formulas (I), (IA), (IA-1), and (IA-2),-L₂- is a bond and R⁴ is methyl.

In one embodiment, in each of Formulas (I), (IA), (IA-1), and (IA-2), R¹is lower alkyl, R² is H, -L₂- is a bond, and R⁴ is alkyl.

In one embodiment, the compounds of the invention have the structuralFormula (II):

and include tautomers, and prodrugs thereof, and pharmaceuticallyacceptable salts, and solvates of said compounds, tautomers, andprodrugs, wherein R³, L₁, L₂, ring A, ring B, R⁵, R⁹, m, n, and p areeach as defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (IIA):

and include tautomers, and prodrugs thereof, and pharmaceuticallyacceptable salts, and solvates of said compounds, tautomers, andprodrugs, wherein R³, L₁, L₃, ring A, ring B, R⁵, R⁹, m, n, and p areeach as defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (IIA-1):

and include tautomers, and prodrugs thereof, and pharmaceuticallyacceptable salts, and solvates of said compounds, tautomers, andprodrugs, wherein R³, L₁, L₃, ring A, ring B, R⁵, R⁹, m, n, and p areeach as defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (IIA-2):

and include tautomers, and prodrugs thereof, and pharmaceuticallyacceptable salts, and solvates of said compounds, tautomers, andprodrugs, wherein R³, L₁, L₃, ring A, ring B, R⁵, R⁹, m, n, and p areeach as defined in Formula (I).

In one embodiment, in each of Formulas (II), (IIA), (IIA-1), and(II-A2), R³ is selected from the group consisting H, alkyl, haloalkyl,and heteroalkyl.

In one embodiment, in each of Formulas (II), (IIA), (IIA-1), and(IIA-2), R³ is selected from the group consisting H, lower alkyl, halolower alkyl, and lower alkyl ether.

In one embodiment, in each of Formulas (II), (IIA), (IIA-1), and(II-A2), R³ is H.

In one embodiment, in each of Formulas (II), (IIA), (IIA-1), and(II-A2):

-L₁- represents a bond or a divalent moiety selected from the groupconsisting of -alkyl-, -haloalkyl-, -heteroalkyl-, and -alkenyl-.

In one embodiment, in each of Formulas (I), (IIA), (IIA-1), and (II-A2):

-L₁- represents a divalent moiety selected from the group consisting of-alkyl-, -haloalkyl-, -heteroalkyl-, and -alkenyl-.

-L₁- represents a divalent moiety selected from the group consisting of-alkyl-, and -haloalkyl-.

In one embodiment, in each of Formulas (II), (IIA), (IIA-1), and(II-A2):

-L₁- represents a bond or a divalent lower alkyl moiety.

In one embodiment, in each of Formulas (II), (IIA), (IIA-1), and(II-A2):

-L₁- represents a bond, —CH₂—, or —CH₂CH₂—.

In one embodiment, in each of Formulas (II), (IIA), (IIA-1), and(II-A2):

-L₁- represents a bond.

In one embodiment, in each of Formulas (II), (IIA), (IIA-1), and(II-A2):

-L₁- represents a divalent lower alkyl moiety.

In one embodiment, in each of Formulas (I), (IIA), (IIA-1), and (II-A2):-L₁- represents —CH₂—.

In one embodiment, in each of Formulas (II), (IIA), (IIA-1), and(II-A2):

-L₁- represents —CH₂CH₂—.

In one embodiment, in each of Formulas (I), (IA), (IA-1), (IA-2), (II),(IIA), (IIA-1), and (IIA-2), n is 0 and m is 1 or more.

In one embodiment, in each of Formulas (I), (IA), (IA-1), (IA-2), (II),(IIA), (IIA-1), and (IIA-2), n is 1 or more, p is 0 or more, and m is 0.

In one embodiment, in each of Formulas (I), (IA), (IA-1), (IA-2), (II),(IIA), (IIA-1), and (IIA-2), n is 1, p is 0 or more, and m is 0 or more.

In one embodiment, in each of Formulas (I), (IA), (IA-1), (IA-2), (II),(IIA), (IIA-1), and (IIA-2), n is 1, p is 0 or more, and m is 0, 1, 2,or 3.

In one embodiment, in each of Formulas (I), (IA), (IA-1), (IA-2), (II),(IIA), (IIA-1), and (IIA-2), n is 1, p is 0 or more, and m is 0, 1, or2.

In one embodiment, in each of Formulas (I), (IA), (IA-1), (IA-2), (II),(IIA), (IIA-1), and (IIA-2), n is 1, p is 0 or more, and m is 0 or 1.

In one embodiment, in each of Formulas (I), (IA), (IA-1), (IA-2), (II),(IIA), (IIA-1), and (IIA-2), n is 1, p is 0 or more, and m is 1.

In one embodiment, in each of Formulas (I), (IA), (IA-1), (IA-2), (II),(IIA), (IIA-1), and (IIA-2), n is 1, p is 0 or more, and m is 2.

In one embodiment, in each of Formulas (I), (IA), (IA-1), (IA-2), (II),(IIA), (IIA-1), and (IIA-2), n is 1, p is 0 or more, and m is 3.

In one embodiment, in each of Formulas (I), (IA), (IA-1), (IA-2), (II),(IIA), (IIA-1), and (IIA-2): -L₁- represents a bond or —CH₂—.

In one embodiment, in each of Formulas (I), (IA), (IA-1), (IA-2), (II),(IIA), (IIA-1), and (IIA-2):

ring A is selected from the group consisting of phenyl, pyridyl,pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridazinyl, thiazolyl,oxazolyl, imidazolyl, pyrazolyl, quinazolinyl, benzofuranyl,benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothienyl, naphthyl,quinolyl, isoquinolyl, indazolyl, indolyl, and thienopyrazolyl.

In one embodiment, in each of Formulas (I), (IA), (IA-1), (IA-2), (II),(IIA), (IIA-1), and (IIA-2):

ring A is selected from the group consisting of phenyl, pyridyl,thienyl, thiazolyl, naphthyl, isoquinolinyl, benzothienyl,benzimidazolyl, indazolyl, indolyl, and thienopyrazolyl.

In one embodiment, in each of Formulas (I), (IA), (IA-1), (IA-2), (II),(IIA), (IIA-1), and (IIA-2):

each -L₃- independently represents a bond or a divalent moiety selectedfrom the group consisting of —NHC(O), —C(O)NH—, —NHS(O)₂—, —S(O)₂NH—,—O—CH₂—, —CH₂—O—, —NHCH₂—, —CH₂NH—, and —CH(CF₃)NH—.

In one embodiment, in each of Formulas (I), (IA), (IA-1), (IA-2), (II),(IIA), (IIA-1), and (IIA-2):

each -L₃- independently represents a bond or a divalent moiety selectedfrom the group consisting of —NHC(O)— and —C(O)NH—.

In one embodiment, in each of Formulas (I), (IA), (IA-1), (IA-2), (II),(IIA), (IIA-1), and (IIA-2):

n is 1 and -L₃- is represents a bond or a divalent moiety selected fromthe group consisting of —NHC(O)— and —C(O)NH—.

In one embodiment, in each of Formulas (I), (IA), (IA-1), (IA-2), (II),(IIA), (IIA-1), and (IIA-2):

n is 1 and -L₃- represents a bond.

In one embodiment, in each of Formulas (I), (IA), (IA-1), (IA-2), (II),(IIA), (IIA-1), and (IIA-2):

n is 1 and -L₃- is a divalent moiety selected from the group consistingof —NHC(O)— and —C(O)NH—.

In one embodiment, in each of Formulas (I), (IA), (IA-1), (IA-2), (II),(IIA), (IIA-1), and (IIA-2):

n is 1 and -L₃- is —C(O)NH—.

In one embodiment, in each of Formulas (I), (IA), (IA-1), (IA-2), (II),(IIA), (IIA-1), and (IIA-2):

n is 1 and -L₃- is —NHC(O)—.

In one embodiment, in each of Formulas (I), (IA), (IA-1), (IA-2), (II),(IIA), (IIA-1), and (IIA-2):

n is 1 or more;

p is 0 or more; and

each ring B is independently selected from the group consisting ofphenyl, pyridyl, pyrimidinyl, oxazolyl, isoxazolyl, pyrazinyl, thienyl,pyrazolyl, furanyl, thiazplyl, pyridazinyl, isothiazolyl, isoxazolyl,isothiazolyl, indolyl, pyrrolopyridinyl, and pyrrolopyrimidinyl.

In one embodiment, in each of Formulas (I), (IA), (IA-1), (IA-2), (11),(IIA), (IIA-1), and (IIA-2):

n is 1 or more;

p is 0 or more; and

each ring B is independently selected from the group consisting ofphenyl, pyridyl, pyrimidinyl, oxazolyl, thiazolyl, isoxazolyl,isothiazolyl, indolyl, pyrrolopyridyl, and pyrrolopyrimidinyl.

In one embodiment, in each of Formulas (I), (IA), (IA-1), (IA-2), (II),(IIA), (IIA-1), and (IIA-2):

m is 1 or more and each R⁵ group is independently selected from thegroup consisting of halogen, —CN, —SF₅, —OSF₅, —N(R⁸)₂, —NR⁸C(O)R⁷,—NR⁸S(O)₂R⁷, —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)OR⁷, —C(O)R⁷, —C(O)₂R⁷,—C(O)N(R⁸)₂, —S(O)R⁷, —S(O)₂R⁷, —S(O)₂N(R⁸)₂, —OR⁷, —SR⁷, lower alkyl,lower haloalkyl, lower heteroalkyl, lower alkynyl, cycloalkyl,heteroaryl, and heterocycloalkyl.

In one embodiment, in each of Formulas (I), (IA), (IA-1), (IA-2), (II),(IIA), (IIA-1), and (IIA-2):

-   -   m is 1 or more and each R⁵ group is independently selected from        the group consisting of halogen, —CN, —SF₅, —N(R⁸)₂, —OR⁷, —SR⁷,        lower alkyl, lower haloalkyl, lower heteroalkyl, lower alkynyl,        and cycloalkyl.

In one embodiment, in each of Formulas (I), (IA), (IA-1), (IA-2), (II),(IIA), (IIA-1), and (IIA-2):

m is 1 or more and each R⁵ group is independently selected from thegroup consisting of halogen, —CN, —SF₅, —N(Rb)₂, —OR⁷, —SR⁷, loweralkyl, lower haloalkyl, lower heteroalkyl, lower alkynyl, andcyclopropyl.

In one embodiment, in each of Formulas (I), (IA), (IA-1), (IA-2), (II),(IIA), (IIA-1), and (IIA-2):

m is 0 or more, n is 1 or more, p is 1 or more, and each R⁹ group isindependently selected from the group consisting of halogen, —CN, —SF₅,—OSF₅, —N(R⁸)₂, —NR⁸C(O)R⁷, —NR⁸S(O)₂R⁷, —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)OR⁷,—C(O)R⁷, —C(O)₂R⁷, —C(O)N(R⁸)₂, —S(O)R⁷, —S(O)₂R⁷, —S(O)₂N(R⁸)₂, —OR⁷,—SR⁷, lower alkyl, lower haloalkyl, lower heteroalkyl, lower alkynyl,aryl, arylalkyl-, cycloalkyl, heteroaryl, heteroarylalkyl-, andheterocycloalkyl.

In one embodiment, in each of Formulas (I), (IA), (IA-1), (IA-2), (II),(IIA), (IIA-1), and (IIA-2):

m is 0 or more, n is 1 or more, p is 1 or more, and each R⁹ group isindependently selected from the group consisting of halogen, —CN, —SF₅,—N(R⁵)₂, —OR⁷, —SR⁷, lower alkyl, lower haloalkyl, lower heteroalkyl,lower alkynyl, phenyl, benzyl, and cycloalkyl.

In one embodiment, in each of Formulas (I), (IA), (IA-1), (IA-2), (II),(IIA), (IIA-1), and (IIA-2):

m is 0 or more, n is 1 or more, p is 1 or more, and each R⁹ group isindependently selected from the group consisting of halogen, —CN, —SF₅,—N(R⁸)₂, —OR⁷, —SR⁷, lower alkyl, lower haloalkyl, lower heteroalkyl,lower alkynyl, phenyl, benzyl, and cyclopropyl.

In one embodiment, in each of Formulas (I), (IA), (IA-1), (IA-2), (II),(IIA), (IIA-1), and (IIA-2), n is 0 and the moiety:

has the form

In one embodiment, in each of Formulas (I), (IA), (IA-1), (IA-2), (II),(IIA), (IIA-1), and (IIA-2):

n is 0;

m is 1 or more;

the moiety:

has the form

-L₁- represents a bond, —CH₂—, or —CH₂CH₂—;

ring A is selected from the group consisting of phenyl, pyridyl,pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridazinyl, thiazolyl,oxazolyl, benzothienyl, benzimidazolyl, indazolyl, indolyl, andthienopyrazolyl; and

each R⁵ group is independently selected from the group consisting ofhalogen, —CN, —SF₅, —N(R⁸)₂, —OR⁷, —SR⁷, lower alkyl, lower haloalkyl,lower heteroalkyl, lower alkynyl, and cycloalkyl.

In one embodiment, in each of Formulas (I), (IA), (IA-1), (IA-2), (II),(IIA), (IIA-1), and (IIA-2):

n is 0;

the moiety:

has the form

-L₁- represents a bond, —CH₂—, or —CH₂CH₂—;

ring A is selected from the group consisting of phenyl, pyridyl,pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridazinyl, thiazolyl,oxazolyl, benzothienyl, benzimidazolyl, indazolyl, indolyl, andthienopyrazolyl;

m is 0 or more; and

each R⁵ group (when present) is independently selected from the groupconsisting of halogen, —CN, —SF₅, —N(R⁸)₂, —OR⁷, —SR⁷, lower alkyl,lower haloalkyl, lower heteroalkyl, lower alkynyl, and cyclopropyl.

In one embodiment, in each of Formulas (I), (IA), (IA-1), (IA-2), (II),(IIA), (IIA-1), and (IIA-2):

ring A is selected from the group consisting of phenyl, pyridyl,pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridazinyl, thiazolyl,oxazolyl, benzothienyl, benzimidazolyl, indazolyl, indolyl, andthienopyrazolyl;

m is 0 or more;

each R⁵ group (when present) is independently selected from the groupconsisting of halogen, —CN, —SF₅, —N(R⁸)₂, —OR⁷, —SR⁷, lower alkyl,lower haloalkyl, lower heteroalkyl, lower alkynyl, and cycloalkyl;

n is 1;

-L₃- represents a bond or a divalent moiety selected from the groupconsisting of —NHC(O)— and —C(O)NH—;

ring B is selected from the group consisting of phenyl, pyridyl,pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridazinyl, thiazolyl,oxazolyl, isoxazolyl, isothiazolyl, indolyl, pyrrolopyridyl, andpyrrolopyrimidinyl;

p is 0 or more; and

each R⁹ group (when present) is independently selected from the groupconsisting of halogen, —CN, —SF₅, —N(R⁸)₂, —OR⁷, —SR⁷, lower alkyl,lower haloalkyl, lower heteroalkyl, lower alkynyl, phenyl, benzyl, andcycloalkyl.

In one embodiment, in each of Formulas (I), (IA), (IA-1), (IA-2), (II),(IIA), (IIA-1), and (IIA-2):

-L₁- represents a bond;

ring A is selected from the group consisting of phenyl, pyridyl,pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridazinyl, thiazolyl,oxazolyl, imidazolyl, pyrazolyl, quinazolinyl, benzofuranyl,benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothienyl, naphthyl,quinolyl, isoquinolyl, indazolyl, indolyl, and thienopyrazolyl.

m is 0 or more;

each R⁵ group (when present) is independently selected from the groupconsisting of halogen, —CN, —SF₅, —N(R⁸)₂, —OR⁷, —SR⁷, lower alkyl,lower haloalkyl, lower heteroalkyl, lower alkynyl, and cyclopropyl;

n is 1;

-L₃- represents a bond or a divalent moiety selected from the groupconsisting of —NHC(O), —C(O)NH—, —NHS(O)₂—, —S(O)₂NH—, —O—CH₂—, —CH₂—O—,—NHCH₂—, —CH₂NH—, and —CH(CF₃)NH—;

ring B is selected from the group consisting of phenyl, pyridyl,pyrimidinyl, oxazolyl, isoxazolyl, pyrazinyl, thienyl, pyrazolyl,furanyl, thiazolyl, pyridazinyl, isothiazolyl, isoxazolyl, isothiazolyl,indolyl, pyrrolopyridinyl, and pyrrolopyrimidinyl;

p is 0 or more; and

each R⁹ group (when present) is independently selected from the groupconsisting of halogen, —CN, —SF₅, —OSF₅, —N(R⁸)₂, —NR⁸C(O)R⁷,—NR⁸S(O)₂R⁷, —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)OR, —C(O)R⁷, —C(O)₂R⁷, —C(O)N(R⁸)₂,—S(O)R⁷, —S(O)₂R, —S(O)₂N(R⁸)₂, —OR⁷, —SR⁷, lower alkyl, lowerhaloalkyl, lower heteroalkyl, lower alkynyl, aryl, arylalkyl-,cycloalkyl, heteroaryl, heteroarylalkyl-, and heterocycloalkyl. In onesuch embodiment, m and p are each independently 0, 1, 2, or 3 up to themaximum number of substitutable hydrogen atoms.

In one such embodiment, each R⁵ (when present) is independently selectedfrom the group consisting of halo.

In one such embodiment, each R⁹ (when present) is independently selectedfrom the group consisting of alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl, halo-substituted heteroalkyl, halo, —O-alkyl, —O-alkyl-OH,—O-deuteroalkyl, —O-heteroalkyl, —O-heteroalkyl-aryl, —O-haloalkyl,heteroaryl, alkyl-substituted heteroaryl, cycloalkyl,—O-alkyl-cycloalkyl, —O-cycloalkyl, OH, heterocycloalkyl,halo-substituted heteroaryl, CN, —S(F)₅, —S-alkyl, and —S(O)₂alkyl.

In another embodiment, the present invention encompasses deuterates ofthe compounds of the invention, or tautomers thereof, or apharmaceutically acceptable salt of said deuterated compound or tautomerof the invention. Specific, non-limiting examples of deuteratedcompounds of the invention are as described and exemplified herein andinclude, deuterated compounds of Formulas (I^(d)), (II^(d)), and(III^(d)). Those of ordinary skill in the art will readily appreciatethat, in addition to the non-limiting examples shown, other availablehydrogen atoms may be deuterated in a similar manner as describedhereinbelow. Such deuterated compounds are also to be considered asbeing among the compounds of the invention. The resulting compound isreferred to herein as a “deuterated” compound of the invention or,alternatively, as “deuterate(s)” of compounds of the invention. Thecompounds of the invention may be deuterated in a manner known to thoseof ordinary skill in the art, e.g., as described herein. Thus, in onenon-limiting embodiment, deuterated compounds of the invention have thestructural Formula (I^(d)):

wherein:

one or more hydrogen atoms present in R¹, R², R³, R⁴, R⁵ (when present)and/or R⁹ (when present), or one or more of any available hydrogenatom(s) present on ring A or ring B (when present) is replaced bydeuterium; and

each of the remaining variables is as defined in Formula (I), or asdescribed in any of the embodiments described herein, e.g., those ofFormulas (IA), (IA-1), (IA-2), (II), (IIA), (IIA-1), and (IIA-2) and thevarious embodiments thereof, are also within the scope of the compoundsof Formula (I^(d)).

For example, in one non-limiting embodiment, in Formula (I^(d)), R¹ is-CD₃ and each of R², R³, R⁴, R⁵, R⁹, -L₁-, -L₂-, -L₃-, ring A, ring B,m, n, and p are as defined in Formula (I) or as in any one of (IA),(IA-1), (IA-2), (II), (II-A), (II-A1), or (II-A2), or the variousembodiments described herein.

As another example, in another non-limiting embodiment, in Formula(I^(d)), R² is D and each of R, R³, R⁴, R⁵, R⁹, -L₁-, -L₂-, -L₃-, ringA, ring B, m, n, and p are as defined in Formula (I) or as in any one of(IA), (IA-1), (IA-2), (II), (II-A), (II-A1), or (II-A2), or the variousembodiments described herein.

As another example, in another non-limiting embodiment, in Formula(I^(d)), R³ is D and each of R¹, R², R⁴, R⁵, R⁹, -L₁-, -L₂-, -L₃-, ringA, ring B, m, n, and p are as defined in Formula (I) or as in any one of(IA), (IA-1), (IA-2), (II), (II-A), (II-A1), or (II-A2), or the variousembodiments described herein.

As another example, in another non-limiting embodiment, in Formula(I^(d)), R⁴ is partially or fully deuterated lower alkyl and each of R¹,R², R³, R⁵, R⁹, -L₁-, -L₂-, -L₃-, ring A, ring B, m, n, and p are asdefined in Formula (I) or as in any one of (IA), (IA-1), (IA-2), (II),(II-A), (II-A1), or (II-A2), or the various embodiments describedherein.

As another example, in another non-limiting embodiment, in Formula(I^(d)), R⁵ is D and each of R¹, R², R³, R⁴, R⁹, -L₁-, -L₂-, -L₃-, ringA, ring B, m, n, and p are as defined in Formula (I) or as in any one of(IA), (IA-1), (IA-2), (II), (II-A), (IT-A1), or (II-A2), or the variousembodiments described herein.

As another example, in another non-limiting embodiment, in Formula(I^(d)), R⁹ is D and each of R¹, R², R³, R⁴, R⁵, -L₁-, -L₂-, -L₃-, ringA, ring B, m, n, and p are as defined in Formula (I) or as in any one of(IA), (IA-1), (IA-2), (II), (II-A), (II-A), or (II-A2), or the variousembodiments described herein.

By way of further illustration, in another non-limiting embodiment,deuterated compounds of the invention have the structural Formula(II^(d)):

wherein:

the moiety —CD₃ represents a deuterated form of the moiety —CH₃; and

each of the remaining variables is as defined in Formula (I), or asdescribed in any of the embodiments described herein, e.g., those offormulas (IA), (IA-1), (IA-2), (II), (II-A), (II-A1), and (II-A2), andthe various embodiments thereof, are also within the scope of thecompounds of Formula (II^(d)).

By way of further illustration, in another non-limiting embodiment,deuterated compounds of the invention have the structural Formula(III^(d)):

wherein:

the moiety -D represents a deuterated form of hydrogen; and

each of the remaining variables is as defined in Formula (I), or asdescribed in any of the embodiments described herein, e.g., those offormulas (IA), (IA-1), (IA-2), (II), (II-A), (II-A1), and (II-A2), andthe various embodiments thereof, are also within the scope of thecompounds of Formula (III^(d)). In one embodiment, in Formula (III^(d)),R³ is D.

By way of further illustration, in another non-limiting embodiment,deuterated compounds of the invention have the structural Formula(IV^(d)):

wherein:

the moiety -D represents a deuterated form of hydrogen; and

each of the remaining variables is as defined in Formula (I), or asdescribed in any of the embodiments described herein, e.g., those offormulas (IA), (IA-1), (IA-2), (II), (II-A), (II-A1), and (II-A2), andthe various embodiments thereof, are also within the scope of thecompounds of Formula (IV^(d)).

In another embodiment, the present invention encompasses a stereoisomeror racemic mixture of a compound of the invention, or a tautomerthereof, or a pharmaceutically acceptable salt of said compound or saidtautomer. It shall be appreciated that, while the present inventionencompasses all stereoisomers and racemic mixtures of the compounds ofthe invention, the stereoconfiguration shown in the structural formulasand in the examples are also contemplated as being within the scope ofthe invention.

In another embodiment, 1 to 3 carbon atoms of the compounds of theinvention may be replaced with 1 to 3 silicon atoms so long as allvalency requirements are satisfied.

In another embodiment, the compounds of the invention are each of thecompounds of the tables below and have a structure shown for thecorresponding example in the preparative examples below.

The present invention includes tautomers and stereoisomers of each ofthe example compounds of the invention, and pharmaceutically acceptablesalts and solvates of said compounds, said stereoisomers, and/or saidtautomers. Such tautomers and stereosiomers of each of the examplecompounds, and pharmaceutically and solvates of said compounds, saidstereoisomers, and/or said tautomers, each represent additionalembodiments of the invention.

In another embodiment, the invention provides a composition comprisingat least one compound of the invention, or a tautomer or stereoisomerthereof, or salt or solvate of said compound, said stereoisomer, or saidtautomer, and a suitable carrier or diluent.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising at least one compound of the invention, or atautomer or stereoisomer thereof, or pharmaceutically acceptable salt orsolvate of said compound, said stereoisomer, or said tautomer, and apharmaceutically acceptable carrier or diluent.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising at least one solvate of a compound of theinvention, or a tautomer or isomer thereof, or pharmaceuticallyacceptable salt or solvate of said compound or said tautomer, and apharmaceutically acceptable carrier or diluent.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising at least one pharmaceutically acceptable salt ofa compound of the invention, or a tautomer or stereoisomer thereof, orpharmaceutically acceptable salt or solvate of said compound, saidstereoisomer, or said tautomer, and a pharmaceutically acceptablecarrier or diluent.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising at least one tautomer of a compound of theinvention, or a tautomer or stereoisomer thereof, or pharmaceuticallyacceptable salt or solvate of said compound, said stereoisomer, or saidtautomer, and a pharmaceutically acceptable carrier or diluent.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising at least one compound of the invention, or atautomer or stereoisomer thereof, or pharmaceutically acceptable salt orsolvate of said compound, said stereoisomer, or said tautomer, togetherwith at least one additional therapeutic agent, and a pharmaceuticallyacceptable carrier or diluent.

Non-limiting examples of additional therapeutic agents for use incombination with the compounds of the invention include drugs selectedfrom the group consisting of: (a) drugs useful for the treatment ofAlzheimer's disease and/or drugs useful for treating one or moresymptoms of Alzheimer's disease, (b) drugs useful for inhibiting thesynthesis A3, and (c) drugs useful for treating neurodegenerativediseases.

Additional non-limiting examples of additional therapeutic agents foruse in combination with the compounds of the invention include drugsuseful for the treatment, prevention, delay of onset, amelioration ofany pathology associated with Aβ and/or a symptom thereof. Non-limitingexamples of pathologies associated with Aβ include: Alzheimer's disease,Down's syndrome, Parkinson's disease, memory loss, memory lossassociated with Alzheimer's disease, memory loss associated withParkinson's disease, attention deficit symptoms, attention deficitsymptoms associated with Alzheimer's disease, Parkinson's disease,and/or Down's syndrome, dementia, stroke, microgliosis and braininflammation, pre-senile dementia, senile dementia, dementia associatedwith Alzheimer's disease, Parkinson's disease, and/or Down's syndrome,progressive supranuclear palsy, cortical basal degeneration,neurodegeneration, olfactory impairment, olfactory impairment associatedwith Alzheimer's disease, Parkinson's disease, and/or Down's syndrome,β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebralhemorrhage, mild cognitive impairment (“MCI”), glaucoma, amyloidosis,type II diabetes, hemodialysis complications (from β₂ microglobulins andcomplications arising therefrom in hemodialysis patients), scrapie,bovine spongiform encephalitis, traumatic brain injury (“TBI”), andCreutzfeld-Jakob disease, comprising administering to said patient atleast one compound of the invention, or a tautomer or isomer thereof, orpharmaceutically acceptable salt or solvate of said compound or saidtautomer, in an amount effective to inhibit said pathology orpathologies.

In embodiments of the invention comprising at least one additionaltherapeutic agent, additional non-limiting examples of additionaltherapeutic agents for use in combination with compounds of theinvention include: muscarinic antagonists (e.g., m₁ agonists (such asacetylcholine, oxotremorine, carbachol, or McNa343), or m₂ antagonists(such as atropine, dicycloverine, tolterodine, oxybutynin, ipratropium,methoctramine, tripitamine, or gallamine)); cholinesterase inhibitors(e.g., acetyl- and/or butyrylchlolinesterase inhibitors such asdonepezil (Aricept®), galantamine (Razadyne®), and rivastigimine(Exelon®); N-methyl-D-aspartate receptor antagonists (e.g., Namenda®(memantine HCl, available from Forrest Pharmaceuticals, Inc.);combinations of cholinesterase inhibitors and N-methyl-D-aspartatereceptor antagonists; gamma secretase modulators; gamma secretaseinhibitors; non-steroidal anti-inflammatory agents; anti-inflammatoryagents that can reduce neuroinflammation; anti-amyloid antibodies (suchas bapineuzemab, Wyeth/Elan); vitamin E; nicotinic acetylcholinereceptor agonists; CB1 receptor inverse agonists or CB1 receptorantagonists; antibiotics; growth hormone secretagogues; histamine H3antagonists; AMPA agonists; PDE4 inhibitors; GABA_(A) inverse agonists;inhibitors of amyloid aggregation; glycogen synthase kinase betainhibitors; promoters of alpha secretase activity; PDE-10 inhibitors;Tau kinase inhibitors (e.g., GSK3beta inhibitors, cdk5 inhibitors, orERK inhibitors); Tau aggregation inhibitors (e.g., Rember®); RAGEinhibitors (e.g., TTP 488 (PF-4494700)); anti-Abeta vaccine; APPligands; agents that upregulate insulin, cholesterol lowering agentssuch as HMG-CoA reductase inhibitors (for example, statins such asAtorvastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin,Pravastatin, Rosuvastatin, Simvastatin) and/or cholesterol absorptioninhibitors (such as Ezetimibe), or combinations of HMG-CoA reductaseinhibitors and cholesterol absorption inhibitors (such as, for example,Vytorin®); fibrates (such as, for example, clofibrate, Clofibride,Etofibrate, and Aluminium Clofibrate); combinations of fibrates andcholesterol lowering agents and/or cholesterol absorption inhibitors;nicotinic receptor agonists; niacin; combinations of niacin andcholesterol absorption inhibitors and/or cholesterol lowering agents(e.g., Simcor® (niacin/simvastatin, available from Abbott Laboratories,Inc.); LXR agonists; LRP mimics; H3 receptor antagonists; histonedeacetylase inhibitors; hsp90 inhibitors; 5-HT4 agonists (e.g.,PRX-03140 (Epix Pharmaceuticals)); 5-HT6 receptor antagonists; mGluR1receptor modulators or antagonists; mGluR5 receptor modulators orantagonists; mGluR2/3 antagonists; Prostaglandin EP2 receptorantagonists; PAI-1 inhibitors; agents that can induce Abeta efflux suchas gelsolin; Metal-protein attenuating compound (e.g, PBT2); and GPR3modulators; and antihistamines such as Dimebolin (e.g., Dimebon®,Pfizer).

In another embodiment, the invention provides a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds of the invention, and effective amount of one or morecholinesterase inhibitors (e.g., acetyl- and/or butyrylchlolinesteraseinhibitors), and a pharmaceutically acceptable carrier.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds of the invention, and effective amount of one or moremuscarinic agonists or antagonists (e.g., m₁ agonists or m₂antagonists), and a pharmaceutically acceptable carrier.

In one embodiment, the invention provides combinations comprising aneffective (i.e., therapeutically effective) amount of one or morecompounds of the invention, in combination with an effective (i.e.,therapeutically effective) amount of one or more compounds selected fromthe group consisting of cholinesterase inhibitors (such as, for example,(±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-onehydrochloride, i.e, donepezil hydrochloride, available as the Aricept®brand of donepezil hydrochloride), N-methyl-D-aspartate receptorinhibitors (such as, for example, Namenda® (memantine HCl));anti-amyloid antibodies (such as bapineuzumab, Wyeth/Elan), gammasecretase inhibitors, gamma secretase modulators, and beta secretaseinhibitors other than the compounds of the invention.

In one embodiment, the invention provides combinations comprising aneffective (i.e., therapeutically effective) amount of one or morecompounds of the invention, in combination with an effective (i.e.,therapeutically effective) amount of one or more compounds selected fromthe group consisting of cholinesterase inhibitors (such as, for example,(±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-onehydrochloride, i.e, donepezil hydrochloride, available as the Aricept®brand of donepezil hydrochloride), N-methyl-D-aspartate receptorinhibitors (such as, for example, Namenda® (memantine HCl)).

In one embodiment, the invention provides combinations comprising aneffective (i.e., therapeutically effective) amount of one or morecompounds of the invention, in combination with an effective (i.e.,therapeutically effective) amount of one or more gamma secretaseinhibitors.

In one embodiment, the invention provides combinations comprising aneffective (i.e., therapeutically effective) amount of one or morecompounds of the invention, in combination with an effective (i.e.,therapeutically effective) amount of one or more gamma secretasemodulators.

In one embodiment, the invention provides combinations comprising aneffective (i.e., therapeutically effective) amount of one or morecompounds of the invention, or a tautomer or stereoisomer thereof, orpharmaceutically acceptable salt or solvate of said compound, saidstereoisomer, or said tautomer, in combination with an effective (i.e.,therapeutically effective) amount of one or more gamma secretaseinhibitors and in further combination with one or more gamma secretasemodulators.

In another embodiment, the invention provides a compound of theinvention, or a tautomer or stereoisomer thereof, or pharmaceuticallyacceptable salt or solvate of said compound, said stereoisomer, or saidtautomer, in pure form, in isolated form, and/or in isolated and pureform.

Prodrugs of the compounds of the invention, or tautomers orstereoisomers thereof, or pharmaceutically acceptable salts or solvatesof said compounds, said stereoisomers, and/or said tautomers, are alsocontemplated as being included within the scope of the invention, andare described more fully below.

Deuterates of the compounds of the invention, or tautomers orstereoisomers of said deuterates, or pharmaceutically acceptable saltsor solvates of said deuterates, said stereoisomers, and/or saidtautomers, are also contemplated as being included within the scope ofthe invention, and are described more fully above.

In another embodiment, the invention provides a method of preparing apharmaceutical composition comprising the step of admixing at least onecompound of the invention, or a tautomer or stereoisomer thereof, orpharmaceutically acceptable salt or solvate of said compound, saidstereoisomer, or said tautomer, and a pharmaceutically acceptablecarrier or diluent.

In another embodiment, the invention provides a method of inhibitingβ-secretase comprising exposing a population of cells expressingβ-secretase to at least one compound of the invention, or a tautomer orstereoisomer thereof, or pharmaceutically acceptable salt or solvate ofsaid compound, said stereoisomer, or said tautomer, in an amounteffective to inhibit β-secretase.

In another embodiment, the invention provides a method of inhibitingβ-secretase in a patient in need thereof comprising administering atleast one compound of the invention, or a tautomer or stereoisomerthereof, or pharmaceutically acceptable salt or solvate of saidcompound, said stereoisomer, or said tautomer, in a therapeuticallyeffective amount to inhibit 3-secretase in said patient.

In another embodiment, the invention provides a method of inhibitingBACE-1 comprising exposing a population of cells expressing BACE-1 to atleast one compound of the invention, or a tautomer or stereoisomerthereof, or pharmaceutically acceptable salt or solvate of said compoundor said tautomer, in an amount effective to inhibit BACE-1 in saidcells. In one such embodiment, said population of cells is in vivo. Inanother such embodiment, said population of cells is ex vivo. In anothersuch embodiment, said population of cells is in vitro.

In another embodiment, the invention provides a method of inhibitingBACE-2 comprising exposing a population of cells expressing BACE-2 to atleast one compound of the invention, or a tautomer or stereoisomerthereof, or pharmaceutically acceptable salt or solvate of said compoundor said tautomer, in an amount effective to inhibit BACE-2 in saidcells. In one such embodiment, said population of cells is in vivo. Inanother such embodiment, said population of cells is ex vivo. In anothersuch embodiment, said population of cells is in vitro.

In another embodiment, the invention provides a method of inhibitingBACE-1 in a patient in need thereof comprising administering to saidpatient at least one compound of the invention, or a tautomer orstereoisomer thereof, or pharmaceutically acceptable salt or solvate ofsaid compound, said stereoisomer, or said tautomer, in a therapeuticallyeffective amount to inhibit BACE-1 in said patient.

In another embodiment, the invention provides a method of inhibitingBACE-2 in a patient in need thereof comprising administering to saidpatient at least one compound of the invention, or a tautomer orstereoisomer thereof, or pharmaceutically acceptable salt or solvate ofsaid compound, said stereoisomer, or said tautomer, in a therapeuticallyeffective amount to inhibit BACE-2 in said patient.

In another embodiment, the invention provides a method of inhibiting theformation of Aβ from APP in a patient in need thereof, comprisingadministering to said patient at least one compound of the invention, ora tautomer or stereoisomer thereof, or pharmaceutically acceptable saltor solvate of said compound, said stereoisomer, or said tautomer, in anamount effective to inhibit said Aβ formation.

In another embodiment, the invention provides a method of inhibiting theformation of Aβ plaque in a patient in need thereof, comprisingadministering to said patient at least one compound of the invention, ora tautomer or stereoisomer thereof, or pharmaceutically acceptable saltor solvate of said compound, said stereoisomer, or said tautomer, in anamount effective to inhibit said Aβ plaque formation.

In another embodiment, the invention provides a method of inhibiting theformation of Aβ fibrils in a patient in need thereof, comprisingadministering to said patient at least one compound of the invention, ora tautomer or stereoisomer thereof, or pharmaceutically acceptable saltor solvate of said compound, said stereoisomer, or said tautomer, in anamount effective to inhibit said Aβ fibril formation.

In another embodiment, the invention provides a method of inhibiting theformation of Aβ oligomers in a patient in need thereof, comprisingadministering to said patient at least one compound of the invention, ora tautomer or stereoisomer thereof, or pharmaceutically acceptable saltor solvate of said compound, said stereoisomer, or said tautomer, in anamount effective to inhibit said Aβ fibril formation.

In another embodiment, the invention provides a method of inhibiting theformation of Aβ fibrils and Aβ oligomers in a patient in need thereof,comprising administering to said patient at least one compound of theinvention, or a tautomer or stereoisomer thereof, or pharmaceuticallyacceptable salt or solvate of said compound, said stereoisomer, or saidtautomer, in an amount effective to inhibit said Aβ fibril formation.

In another embodiment, the invention provides a method of inhibiting theformation of senile plaques and/or neurofibrillary tangles in a patientin need thereof, comprising administering to said patient at least onecompound of the invention, or a tautomer or stereoisomer thereof, orpharmaceutically acceptable salt or solvate of said compound, saidstereoisomer, or said tautomer, in an amount effective to inhibit saidAβ fibril formation.

In another embodiment, the invention provides a method of treating,preventing, and/or delaying the onset of an amyloid β pathology (“Aβpathology”) and/or one or more symptoms of said pathology comprisingadministering at least one compound of the invention, or a tautomer orstereoisomer thereof, or pharmaceutically acceptable salt or solvate ofsaid compound, said stereoisomer, or said tautomer, to a patient in needthereof in an amount effective to treat said pathology.

In another embodiment, the invention provides a method of treating,preventing, and/or delaying the onset of one or more pathologiesassociated with Aβ and/or one or more symptoms of one or morepathologies associated with Aβ. Non-limiting examples of pathologiesassociated with AR include: Alzheimer's disease, Down's syndrome,Parkinson's disease, memory loss, memory loss associated withAlzheimer's disease, memory loss associated with Parkinson's disease,attention deficit symptoms, attention deficit symptoms associated withAlzheimer's disease, Parkinson's disease, and/or Down's syndrome,dementia, stroke, microgliosis and brain inflammation, pre-seniledementia, senile dementia, dementia associated with Alzheimer's disease,Parkinson's disease, and/or Down's syndrome, progressive supranuclearpalsy, cortical basal degeneration, neurodegeneration, olfactoryimpairment, olfactory impairment associated with Alzheimer's disease,Parkinson's disease, and/or Down's syndrome, β-amyloid angiopathy,cerebral amyloid angiopathy, hereditary cerebral hemorrhage, mildcognitive impairment (“MCI”), glaucoma, amyloidosis, type II diabetes,diabetes-associated amyloidogenesis, hemodialysis complications (from β₂microglobulins and complications arising therefrom in hemodialysispatients), scrapie, bovine spongiform encephalitis, traumatic braininjury (“TBI”) and Creutzfeld-Jakob disease, comprising administering tosaid patient at least one compound of the invention, or a tautomer orstereoisomer thereof, or pharmaceutically acceptable salt or solvate ofsaid compound, said stereoisomer, or said tautomer, in an amounteffective to inhibit said pathology or pathologies.

In one embodiment, the invention provides a method of treating one ormore neurodegenerative diseases, comprising administering an effective(i.e., therapeutically effective) amount of one or more compounds of theinvention (or a tautomer or stereoisomer thereof, or pharmaceuticallyacceptable salt or solvate of said compound, said stereoisomer, or saidtautomer), alone or optionally in combination with one or moreadditional therapeutic agents useful in treating one or moreneurodegenerative diseases, to a patient in need of such treatment.

In one embodiment, the invention provides a method of inhibiting thedeposition of amyloid protein (e.g., amyloid beta protein) in, on oraround neurological tissue (e.g., the brain), comprising administeringan effective (i.e., therapeutically effective) amount of one or morecompounds of the invention (or a tautomer or stereoisomer thereof, orpharmaceutically acceptable salt or solvate of said compound, saidstereoisomer, or said tautomer), alone or optionally in combination withone or more additional therapeutic agents useful in treating one or moreneurodegenerative diseases, to a patient in need of such treatment.

In one embodiment, the invention provides a method of treatingAlzheimer's disease, comprising administering an effective (i.e.,therapeutically effective) amount of one or more compounds of theinvention (or a tautomer or stereoisomer thereof, or pharmaceuticallyacceptable salt or solvate of said compound, said stereoisomer, or saidtautomer), alone or optionally in combination with one or moreadditional therapeutic agents useful in treating Alzheimer's disease, toa patient in need of such treatment.

In one embodiment, the invention provides a method of treating Down'ssyndrome, comprising administering an effective (i.e., therapeuticallyeffective) amount of one or more compounds of the invention (or atautomer or stereoisomer thereof, or pharmaceutically acceptable salt orsolvate of said compound, said stereoisomer, or said tautomer), alone oroptionally in combination with an effective (e.g., therapeuticallyeffective) amount of one or more additional active agents useful intreating Down's syndrome, to a patient in need of such treatment.

In one embodiment, the invention provides a method of treating mildcognitive impairment, comprising administering an effective amount ofone or more (e.g., one) compounds of the invention (or a tautomer orstereoisomer thereof, or pharmaceutically acceptable salt or solvate ofsaid compound, said stereoisomer, or said tautomer), alone or optionallyin combination with one or more additional active agents useful intreating mild cognitive impairment, to a patient in need of suchtreatment.

In one embodiment, the invention provides a method of treating glaucoma,comprising administering an effective amount of one or more (e.g., one)compounds of the invention (or a tautomer or stereoisomer thereof, orpharmaceutically acceptable salt or solvate of said compound, saidstereoisomer, or said tautomer), alone or optionally in combination withone or more additional active agents useful in treating glaucoma, to apatient in need of such treatment.

In one embodiment, the invention provides a method of treating cerebralamyloid angiopathy, comprising administering an effective amount of oneor more (e.g., one) compounds of the invention (or a tautomer orstereoisomer thereof, or pharmaceutically acceptable salt or solvate ofsaid compound, said stereoisomer, or said tautomer), alone or optionallyin combination with one or more additional active agents useful intreatingcerebral amyloid angiopathy, to a patient in need of suchtreatment. to a patient in need of treatment.

In one embodiment, the invention provides a method of treating stroke,comprising administering an effective amount of one or more (e.g., one)compounds of the invention (or a tautomer or stereoisomer thereof, orpharmaceutically acceptable salt or solvate of said compound, saidstereoisomer, or said tautomer), alone or optionally in combination withone or more additional active agents useful in treating stroke, to apatient in need of such treatment.

In one embodiment, the invention provides a method of treating dementia,comprising administering an effective amount of one or more (e.g., one)compounds of the invention (or a tautomer or stereoisomer thereof, orpharmaceutically acceptable salt or solvate of said compound, saidstereoisomer, or said tautomer), alone or optionally in combination withone or more additional active agents useful in treating dementia, to apatient in need of such treatment. to a patient in need of treatment.

In one embodiment, the invention provides a method of treatingmicrogliosis, comprising administering an effective amount of one ormore (e.g., one) compounds of the invention (or a tautomer orstereoisomer thereof, or pharmaceutically acceptable salt or solvate ofsaid compound, said stereoisomer, or said tautomer), alone or optionallyin combination with one or more additional active agents useful intreating microgliosis, to a patient in need of such treatment.

In one embodiment, the invention provides a method of treating braininflammation, comprising administering an effective amount of one ormore (e.g., one) compounds of the invention (or a tautomer orstereoisomer thereof, or pharmaceutically acceptable salt or solvate ofsaid compound, said stereoisomer, or said tautomer), alone or optionallyin combination with one or more additional active agents useful intreating brain inflammation, to a patient in need of such treatment.

In one embodiment, the invention provides a method of treating traumaticbrain injury, comprising administering an effective amount of one ormore (e.g., one) compounds of the invention (or a tautomer orstereoisomer thereof, or pharmaceutically acceptable salt or solvate ofsaid compound, said stereoisomer, or said tautomer), alone or optionallyin combination with one or more additional active agents useful intreating traumatic brain injury, to a patient in need of such treatment.

In one embodiment, the invention provides a method of treating olfactoryfunction loss, comprising administering an effective amount of one ormore (e.g., one) compounds of the invention (or a tautomer orstereoisomer thereof, or pharmaceutically acceptable salt or solvate ofsaid compound, said stereoisomer, or said tautomer), alone or optionallyin combination with one or more additional active agents useful intreating olfactory function loss, to a patient in need of suchtreatment.

In one embodiment, in each of the above recited methods of treatment,said one or more additional therapeutic agent is selected from one ormore cholinesterase inhibitors (such as, for example,(t)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-onehydrochloride, i.e, donepezil hydrochloride, available as the Aricept®brand of donepezil hydrochloride).

In one embodiment, in each of the above recited methods of treatment,said one or more additional therapeutic agent is selected from the groupconsisting of Aβ antibody inhibitors, gamma secretase inhibitors, gammasecretase modulators, and beta secretase inhibitors other than acompound of the invention.

In one embodiment, in each of the above recited methods of treatment,said one or more additional therapeutic agent is Exelon (rivastigmine).

In one embodiment, in each of the above recited methods of treatment,said one or more additional therapeutic agent is selected from Cognex(tacrine).

In one embodiment, in each of the above recited methods of treatment,said one or more additional therapeutic agent is selected from Taukinase inhibitor (e.g., GSK3beta inhibitor, cdk5 inhibitor, ERKinhibitor).

In one embodiment, in each of the above recited methods of treatment,said one or more additional therapeutic agent is selected from ananti-Aβ vaccine.

In one embodiment, in each of the above recited methods of treatment,said one or more additional therapeutic agent is selected from an APPligand.

In one embodiment, in each of the above recited methods of treatment,said one or more additional therapeutic agent is selected from one ormore agents that upregulate insulin degrading enzyme and/or neprilysin.

In one embodiment, in each of the above recited methods of treatment,said one or more additional therapeutic agent is selected from one ormore cholesterol lowering agents. Non-limiting examples of saidcholesterol lowerin agents include: statins such as Atorvastatin,Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin,Rosuvastatin, Simvastatin, and cholesterol absorption inhibitors such asEzetimibe and phytonutrients.

In one embodiment, in each of the above recited methods of treatment,said one or more additional therapeutic agent is selected from one ormore fibrates. Non-limiting examples of said fibtrates includeclofibrate, Clofibride, Etofibrate, and Aluminium Clofibrate.

In one embodiment, in each of the above recited methods of treatment,said one or more additional therapeutic agent is selected from one ormore LXR agonists.

In one embodiment, in each of the above recited methods of treatment,said one or more additional therapeutic agent is selected from one ormore LRP mimics.

In one embodiment, in each of the above recited methods of treatment,said one or more additional therapeutic agent is selected from one ormore 5-HT6 receptor antagonists.

In one embodiment, in each of the above recited methods of treatment,said one or more additional therapeutic agent is selected from one ormore nicotinic receptor agonists.

In one embodiment, in each of the above recited methods of treatment,said one or more additional therapeutic agent is selected from one ormore H3 receptor antagonists.

In one embodiment, in each of the above recited methods of treatment,said one or more additional therapeutic agent is selected from one ormore histone deacetylase inhibitors.

In one embodiment, in each of the above recited methods of treatment,said one or more additional therapeutic agent is selected from one ormore hsp90 inhibitors.

In one embodiment, in each of the above recited methods of treatment,said one or more additional therapeutic agent is selected from one ormore m1 muscarinic receptor agonists.

In one embodiment, in each of the above recited methods of treatment,said one or more additional therapeutic agent is selected from one ormore 5-HT6 receptor antagonists, mGluR1, and mGluR5 positive allostericmodulators or agonists.

In one embodiment, in each of the above recited methods of treatment,said one or more additional therapeutic agent is selected from one ormore mGluR2/3 antagonists.

In one embodiment, in each of the above recited methods of treatment,said one or more additional therapeutic agent is selected from one ormore anti-inflammatory agents that can reduce neuroinflammation.

In one embodiment, in each of the above recited methods of treatment,said one or more additional therapeutic agent is selected from one ormore prostaglandin EP2 receptor antagonists.

In one embodiment, in each of the above recited methods of treatment,said one or more additional therapeutic agent is selected from one ormore PAI-1 inhibitors.

In one embodiment, in each of the above recited methods of treatment,said one or more additional therapeutic agent is selected from one ormore agents that can induce Aβ efflux. One non-limiting example of anagent that can induce Aβ influx is gelsolin.

In one embodiment, the invention provides a kit comprising, in separatecontainers, in a single package, pharmaceutical compositions for use incombination, wherein one container comprises an effective amount of acompound of the invention (or a tautomer or stereoisomer thereof, orpharmaceutically acceptable salt or solvate of said compound, saidstereoisomer, or said tautomer) in a pharmaceutically acceptablecarrier, and, optionally, another container (i.e., a second container)comprises an effective amount of another pharmaceutically activeingredient (as described below), the combined quantities of the compoundof the invention and the other pharmaceutically active ingredient beingeffective to: (a) treat Alzheimer's disease, or (b) inhibit thedeposition of amyloid protein (e.g., amyloid beta protein) in, on oraround neurological tissue (e.g., the brain), or (c) treatneurodegenerative diseases, or (d) inhibit BACE.

In its various embodiments, the invention provides any one of themethods disclosed above and below wherein the compound(s) of theinvention is a compound or compounds selected from the group consistingof the exemplary compounds of the invention described below.

In its various embodiments, the invention provides any one of thepharmaceutical compositions disclosed above and below wherein thecompound(s) of the invention is a compound or compounds selected fromthe group consisting of the exemplary compounds of the inventiondescribed below.

Other embodiments of this invention are directed to any one of theembodiments above or below that are directed to compounds of theinvention, or the use of compounds of the invention (e.g. theembodiments directed to methods of treatment, pharmaceuticalcompositions and kits).

In another embodiment, the invention provides for the use of a compoundof the invention, or a tautomer or stereoisomer thereof, orpharmaceutically acceptable salt or solvate of said compound, saidstereoisomer, or said tautomer, in the manufacture of a medicament foruse in the treatment, the delay of onset, and/or the prevention of oneor more Aβ pathologies and/or in the treatment, the delay of onset,and/or the prevention of one or more symptoms of one or more Aβpathologies.

DEFINITIONS

The terms used herein have their ordinary meaning and the meaning ofsuch terms is independent at each occurrence thereof. Thatnotwithstanding and except where stated otherwise, the followingdefinitions apply throughout the specification and claims. Chemicalnames, common names and chemical structures may be used interchangeablyto describe that same structure. These definitions apply regardless ofwhether a term is used by itself or in combination with other terms,unless otherwise indicated. Hence the definition of“alkyl” applies to“alkyl” as well as the “alkyl” portion of “hydroxyalkyl”, “haloalkyl”,arylalkyl-, alkylaryl-, “alkoxy” etc.

It shall be understood that, in the various embodiments of the inventiondescribed herein, any variable not specifically defined in the contextof the embodiment is as defined in Formula (I). Any carbon as well asheteroatom with unsatisfied valences in the text, schemes, examples andTables herein is assumed to have the sufficient number of hydrogenatom(s) to satisfy the valences.

As described herein, the “example compounds of the invention” (or“example compounds” or “examples”) include, collectively andindividually, each of the compounds set forth with example numbers inthe preparative examples.

As described herein, variables such as R¹, R², R³, and R⁴ may beunsubstituted or substituted with one or more R⁵ groups. It shall beunderstood that the upper limit of the number of substituents (referredto in the phrase “one or more substituents”) is the number of availablehydrogen atoms on the relevant moiety (R¹, R², R³, or R⁴) that areavailable for replacement by a substituent which will result in achemically stable moiety.

As described herein, one or more of the variables -L₁-, -L₂-, and -L₃-of the general formulae optionally independently represent a bond. Itshall be understood that where such a variable represents a bond, themoieties which are shown connected by that variable are directlyattached by covalent bond. Thus, by way of non-limiting illustration, acompound of Formula (I) wherein -L₁-, -L₂- and -L₃- each represent abond can be shown as:

The moiety

which may be optionally substituted as described herein, represents aring referred to herein as “ring A.”

The moiety

which may be optionally substituted as described herein, represents aring referred to herein as “ring B.”

“At least one” means one or more than one, for example, 1, 2, or 3, orin another example, 1 or 2, or in another example 1.

In the various Formulas of the compounds of the invention, e.g., inFormula (I), m, n, and p are each independently selected integers,wherein:

m is 0 or more;

n is 0 or more; and

p is 0 or more,

wherein the maximum value of the sum of m and n is the maximum number ofavailable substitutable hydrogen atoms on ring A, and wherein themaximum value of p is the maximum number of available substitutablehydrogen atoms on ring B. Except for salt forms, the “maximum number ofavailable substitutable hydrogen atoms” refers to the maximum numberthat will result in a neutral molecule.

By way of non-limiting illustration, when ring A is a

group, the maximum value of the sum of m and n 17. When ring A is a

group, the maximum value of the sum of m and n is 3.

In the compounds of the invention, e.g., in Formula (I), each of ring Aand ring B (when present) is selected from the group consisting of amonocyclic aryl, a monocyclic heteroaryl, a monocyclic cycloalkyl, amonocyclic cycloalkenyl, a monocyclic heterocycloalkyl, a monocyclicheterocycloalkenyl, and a multicyclic group, each of which groups may beunsubstituted or optionally further substituted as shown in Formula (I).

As used herein, the term “monocyclic aryl” refers to phenyl.

As used herein, the term “monocyclic heteroaryl” refers to a 4- to7-membered monocyclic heteroaryl group comprising from 1 to 4 ringheteroatoms, said ring heteroatoms being independently selected from thegroup consisting of N, O, and S, and oxides thereof. The point ofattachment to the parent moiety is to any available ring carbon or ringheteroatom. Non-limiting examples of monocyclic heteroaryl moitiesinclude pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridazinyl,pyridone, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl,furazanyl, pyrrolyl, pyrazolyl, triazolyl, thiadiazolyl (e.g.,1,2,4-thiadiazolyl), pyrazinyl, pyridazinyl, imidazolyl, and triazinyl(e.g., 1,2,4-triazinyl), and oxides thereof.

As used herein, the term “monocyclic cycloalkyl” refers to a 3- to7-membered monocyclic cycloalkyl group. Non-limiting examples ofmonocyclic cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and cycloheptyl.

As used herein, the term “monocyclic cycloalkenyl” refers to anon-aromatic 3- to 7-membered cycloalkyl group which contains one ormore carbon-carbon double bonds. Non-limiting examples includecyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, andcycloheptenyl.

As used herein, the term “monocyclic heterocycloalkyl” refers to a 4- to7-membered monocyclic heterocycloalkyl group comprising from 1 to 4 ringheteroatoms, said ring heteroatoms being independently selected from thegroup consisting of N, N-oxide, O, S, S-oxide, S(O), and S(O)₂. Thepoint of attachment to the parent moiety is to any available ring carbonor ring heteroatom. Non-limiting examples of monocyclic heterocycloalkylgroups include piperidyl, oxetanyl, pyrrolidinyl, piperazinyl,morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl,tetrahydrofuranyl, tetrahydrothiophenyl, beta lactam, gamma lactam,delta lactam, beta lactone, gamma lactone, delta lactone, andpyrrolidinone, and oxides thereof.

Non-limiting examples of lower alkyl-substituted oxetanyl include themoiety:

As used herein, the term “monocyclic heterocycloalkenyl” refers to a 4-to 7-membered monocyclic heterocycloalkenyl group comprising from 1 to 4ring heteroatoms, said ring heteroatoms being independently selectedfrom the group consisting of N, N-oxide, O, S, S-oxide, S(O), and S(O)₂.The point of attachment to the parent moiety is to any available ringcarbon or ring heteroatom. Non-limiting examples of monocyclicheterocycloalkenyl groups include 1,2,3,4-tetrahydropyridinyl,1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl,1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl,2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl,dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl,dihydrofuranyl, fluorodihydrofuranyl, dihydrothiophenyl, anddihydrothiopyranyl, and oxides thereof.

As used herein, the term “multicyclic group” refers to a fused ringsystem comprising two (bicyclic), three (tricyclic), or more fusedrings, wherein each ring of the fused ring system is independentlyselected from the group consisting of phenyl, monocyclic heteroaryl,monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclicheterocycloalkyl, and monocyclic heterocycloalkenyl. The point ofattachment to the parent moiety is to any available ring carbon or (ifpresent) ring heteroatom on any of the fused rings.

It shall be understood that each of the following multicyclic groupspictured may be unsubstituted or substituted, as described herein. Onlythe point of attachment to the parent moiety is shown by the wavy line.

The term multicyclic groups includes bicyclic aromatic groups.Non-limiting examples of multicyclic groups which are bicyclic aromaticgroups include:

The term multicyclic groups includes bicyclic heteroaromatic groupscomprising from 1 to 3 or more ring heteroatoms, each said ringheteroatom being independently selected from the group consisting of N,O, and S, S(O), S(O)₂, and oxides of N, O, and S, and oxides thereof.Non-limiting examples of multicyclic groups which are bicyclicheteroaromatic groups comprising from 1 to 3 ring heteroatoms, each saidring heteroatom being independently selected from N, O, and S includethe following, and oxides thereof:

The term multicyclic groups includes saturated bicyclic cycloalkylgroups. Non-limiting examples of multicyclic groups which are saturatedbicyclic cycloalkyl groups include the following:

The term multicyclic group includes partially unsaturated bicycliccycloalkyl groups.

Non-limiting examples of multicyclic groups which comprise partiallyunsaturated bicyclic cycloalkyl groups include the following:

The term multicyclic groups includes partially or fully saturatedbicyclic groups comprising from 1 to 3 ring heteroatoms, each said ringheteroatom is independently selected from the group consisting of N, O,and S, S(O), S(O)₂, and oxides of N and S. Such rings may alsooptionally contain one or more oxo groups, as defined herein.Non-limiting examples of multicyclic groups which are partially or fullysaturated bicyclic groups comprising from 1 to 3 ring heteroatoms, eachsaid ring heteroatom being independently selected from N, O, and Sinclude the following, and oxides thereof:

The term multicyclic groups includes aromatic tricyclic groups,cycloalkyl tricyclic groups, as well as heteroaromatic and partially andfully saturated tricyclic groups. For tricyclic groups comprising ringheteroatoms, said tricyclic groups comprise one or more (e.g., from 1 to5) ring heteroatoms, wherein each said ring heteroatom is independentlyselected from N, O, and S, S(O), S(O)₂, and oxides of N, O, and S:Non-limiting examples of tricyclic multicyclic groups include thefollowing, and, where possible, oxides thereof:

“Patient” includes both human and non-human animals. Non-human animalsinclude those research animals and companion animals such as mice,primates, monkeys, great apes, canine (e.g., dogs), and feline (e.g.,house cats).

“Pharmaceutical composition” (or “pharmaceutically acceptablecomposition”) means a composition suitable for administration to apatient. Such compositions may contain the neat compound (or compounds)of the invention or mixtures thereof, or salts, solvates, prodrugs,isomers, or tautomers thereof, or they may contain one or morepharmaceutically acceptable carriers or diluents. The term“pharmaceutical composition” is also intended to encompass both the bulkcomposition and individual dosage units comprised of more than one(e.g., two) pharmaceutically active agents such as, for example, acompound of the present invention and an additional agent selected fromthe lists of the additional agents described herein, along with anypharmaceutically inactive excipients. The bulk composition and eachindividual dosage unit can contain fixed amounts of the afore-said “morethan one pharmaceutically active agents”. The bulk composition ismaterial that has not yet been formed into individual dosage units. Anillustrative dosage unit is an oral dosage unit such as tablets, pillsand the like. Similarly, the herein-described method of treating apatient by administering a pharmaceutical composition of the presentinvention is also intended to encompass the administration of theafore-said bulk composition and individual dosage units.

“Halogen” means fluorine, chlorine, bromine, or iodine. Preferred arefluorine, chlorine and bromine.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.“Lower alkyl” means a group having about 1 to about 6 carbon atoms inthe chain which may be straight or branched. “Alkyl” may beunsubstituted or optionally substituted by one or more substituentswhich may be the same or different, each substituent being as describedherein or independently selected from the group consisting of halo,alkyl, haloalkyl, spirocycloalkyl, aryl, cycloalkyl, cyano, hydroxy,alkoxy, alkylthio, amino, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂,—O—C(O)-alkyl, —O—C(O)-aryl, —O—C(O)-cycloalkyl, carboxy and—C(O)O-alkyl. Non-limiting examples of suitable alkyl groups includemethyl, ethyl, n-propyl, isopropyl and t-butyl.

“Haloalkyl” means an alkyl as defined above wherein one or more hydrogenatoms on the alkyl is replaced by a halo group defined above.

“Heteroalkyl” means an alkyl moiety as defined above, having one or morecarbon atoms, for example one, two or three carbon atoms, replaced withone or more heteroatoms, which may be the same or different, where thepoint of attachment to the remainder of the molecule is through a carbonatom of the heteroalkyl radical. Suitable such heteroatoms include O, S,S(O), S(O)₂, and —NH—, —N(alkyl)-. Non-limiting examples include ethers,thioethers, amines, hydroxymethyl, 3-hydroxypropyl, 1,2-dihydroxyethyl,2-methoxyethyl, 2-aminoethyl, 2-dimethylaminoethyl, and the like.

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkenyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 6 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkenyl chain. “Lower alkenyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. “Alkenyl” may be unsubstituted or optionally substituted byone or more substituents which may be the same or different, eachsubstituent being independently selected from the group consisting ofhalo, alkyl, aryl, cycloalkyl, cyano, alkoxy and —S(alkyl). Non-limitingexamples of suitable alkenyl groups include ethenyl, propenyl,n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

“Alkylene” means a difunctional group obtained by removal of a hydrogenatom from an alkyl group that is defined above. Non-limiting examples ofalkylene include methylene, ethylene and propylene. More generally, thesuffix “ene” on alkyl, aryl, hetercycloalkyl, etc. indicates a divalentmoiety, e.g., —CH₂CH₂— is ethylene, and

is para-phenylene.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 4 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. “Lower alkynyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkynyl groups includeethynyl, propynyl, 2-butynyl and 3-methylbutynyl. “Alkynyl” may beunsubstituted or optionally substituted by one or more substituentswhich may be the same or different, each substituent being independentlyselected from the group consisting of alkyl, aryl and cycloalkyl.

“Alkenylene” means a difunctional group obtained by removal of ahydrogen from an alkenyl group that is defined above. Non-limitingexamples of alkenylene include —CH═CH—, —C(CH₃)═CH—, and —CH═CHCH₂—.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. The aryl group can be optionally substituted with oneor more “ring system substituents” which may be the same or different,and are as defined herein. Non-limiting examples of suitable aryl groupsinclude phenyl and naphthyl.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one or more of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or more“ring system substituents” which may be the same or different, and areas defined herein. The prefix aza, oxa or thia before the heteroarylroot name means that at least a nitrogen, oxygen or sulfur atomrespectively, is present as a ring atom. A nitrogen atom of a heteroarylcan be optionally oxidized to the corresponding N-oxide. “Heteroaryl”may also include a heteroaryl as defined above fused to an aryl asdefined above. Non-limiting examples of suitable heteroaryls includepyridyl, pyrazinyl, furanyl, thienyl (alternatively referred to asthiophenyl), pyrimidinyl, pyridone (including N-substituted pyridones),isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl,pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl,pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl,imidazo[1,2-a]pyridinyl, imidazo[2, I-b]thiazolyl, benzofurazanyl,indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like. The term “heteroaryl” alsorefers to partially saturated heteroaryl moieties such as, for example,tetrahydroisoquinolyl, tetrahydroquinolyl and the like.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined herein. Non-limiting examples of suitable monocycliccycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyland the like. Non-limiting examples of suitable multicyclic cycloalkylsinclude 1-decalinyl, norbornyl, adamantyl and the like. Furthernon-limiting examples of cycloalkyl include the following:

“Cycloalkenyl” means a non-aromatic mono or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms which contains at least one carbon-carbon double bond.Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. Thecycloalkenyl can be optionally substituted with one or more “ring systemsubstituents” which may be the same or different, and are as definedabove. Non-limiting examples of suitable monocyclic cycloalkenylsinclude cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and thelike. Non-limiting example of a suitable multicyclic cycloalkenyl isnorbornylenyl.

“Heterocycloalkyl” (or “heterocyclyl”) means a non-aromatic saturatedmonocyclic or multicyclic ring system comprising about 3 to about 10ring atoms, preferably about 5 to about 10 ring atoms, in which one ormore of the atoms in the ring system is an element other than carbon,for example nitrogen, oxygen or sulfur, alone or in combination. Thereare no adjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocyclyls contain about 5 to about 6 ring atoms. Theprefix aza, oxa or thia before the heterocyclyl root name means that atleast a nitrogen, oxygen or sulfur atom respectively is present as aring atom. Any —NH in a heterocyclyl ring may exist protected such as,for example, as an —N(Boc), —N(CBz), —N(Tos) group and the like; suchprotections are also considered part of this invention. The heterocyclylcan be optionally substituted by one or more “ring system substituents”which may be the same or different, and are as defined herein. Thenitrogen or sulfur atom of the heterocyclyl can be optionally oxidizedto the corresponding N-oxide, S-oxide or S,S-dioxide. Thus, the term“oxide,” when it appears in a definition of a variable in a generalstructure described herein, refers to the corresponding N-oxide,S-oxide, or S,S-dioxide. Non-limiting examples of suitable monocyclicheterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl,morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl,tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like.“Heterocyclyl” also includes rings wherein ═O replaces two availablehydrogens on the same carbon atom (i.e., heterocyclyl includes ringshaving a carbonyl group in the ring). Such ═O groups may be referred toherein as “oxo,” as described below.

“Heterocycloalkenyl” (or “heterocyclenyl”) means a non-aromaticmonocyclic or multicyclic ring system comprising about 3 to about 10ring atoms, preferably about 5 to about 10 ring atoms, in which one ormore of the atoms in the ring system is an element other than carbon,for example nitrogen, oxygen or sulfur atom, alone or in combination,and which contains at least one carbon-carbon double bond orcarbon-nitrogen double bond. There are no adjacent oxygen and/or sulfuratoms present in the ring system. Preferred heterocyclenyl rings containabout 5 to about 6 ring atoms. The prefix aza, oxa or thia before theheterocyclenyl root name means that at least a nitrogen, oxygen orsulfur atom respectively is present as a ring atom. The heterocyclenylcan be optionally substituted by one or more ring system substituents,wherein “ring system substituent” is as defined above. The nitrogen orsulfur atom of the heterocyclenyl can be optionally oxidized to thecorresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples ofsuitable heterocyclenyl groups include 1,2,3,4-tetrahydropyridinyl,1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl,1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl,2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl,dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl,dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl,dihydrothiophenyl, dihydrothiopyranyl, and the like. “Heterocyclenyl”also includes rings wherein ═O replaces two available hydrogens on thesame carbon atom (i.e., heterocyclenyl includes rings having a carbonylgroup in the ring). Example of such moiety is pyrrolidenone (orpyrrolone):

It should be noted that in hetero-atom containing ring systems of thisinvention, there are no hydroxyl groups on carbon atoms adjacent to a N,O or S, as well as there are no N or S groups on carbon adjacent toanother heteroatom. Thus, for example, in the ring:

there is no —OH attached directly to carbons marked 2 and 5.

“Arylcycloalkyl” (or “arylfused cycloalkyl”) means a group derived froma fused aryl and cycloalkyl as defined herein. Preferred arylcycloalkylsare those wherein aryl is phenyl (which may be referred to as“benzofused”) and cycloalkyl consists of about 5 to about 6 ring atoms.The arylcycloalkyl can be optionally substituted as described herein.Non-limiting examples of suitable arylcycloalkyls include indanyl (abenzofused cycloalkyl) and 1,2,3,4-tetrahydronaphthyl and the like. Thebond to the parent moiety is through a non-aromatic carbon atom.

“Arylheterocycloalkyl” (or “arylfused heterocycloalkyl”) means a groupderived from a fused aryl and heterocycloalkyl as defined herein.Preferred arylheterocycloalkyls are those wherein aryl is phenyl (whichmay be referred to as “benzofused”) and heterocycloalkyl consists ofabout 5 to about 6 ring atoms. The arylheterocycloalkyl can beoptionally substituted, and/or contain the oxide or oxo, as describedherein. Non-limiting examples of suitable arylfused heterocycloalkylsinclude:

The bond to the parent moiety is through a non-aromatic carbon atom.

It is also understood that the terms “arylfused aryl”, “arylfusedcycloalkyl”, “arylfused cycloalkenyl”, “arylfused heterocycloalkyl”,arylfused heterocycloalkenyl”, “arylfused heteroaryl”, “cycloalkylfusedaryl”, “cycloalkylfused cycloalkyl”, “cycloalkylfused cycloalkenyl”,“cycloalkylfused heterocycltoalkyl”, “cycloalkylfusedheterocycloalkenyl”, “cycloalkylfused heteroaryl, “cycloalkenylfusedaryl”, “cycloalkenylfused cycloalkyl”, “cycloalkenylfused cycloalkenyl”,“cycloalkenylfused heterocycloalkyl”, “cycloalkenylfusedheterocycloalkenyl”, “cycloalkenylfused heteroaryl”,“heterocycloalkylfused aryl”, “heterocycloalkylfused cycloalkyl”,“heterocycloalkylfused cycloalkenyl”, “heterocycloalkylfusedheterocycloalkyl”, “heterocycloalkylfused heterocycloalkenyl”,“heterocycloalkylfused heteroaryl”, “heterocycloalkenylfused aryl”,“heterocycloalkenylfused cycloalkyl”, “heterocycloalkenylfusedcycloalkenyl”, “heterocycloalkenylfused heterocycloalkyl”,“heterocycloalkenylfused heterocycloalkenyl”, “heterocycloalkenylfusedheteroaryl”, “heteroarylfused aryl”, “heteroarylfused cycloalkyl”,“heteroarylfused cycloalkenyl”, “heteroarylfused heterocycloalkyl”,“heteroarylfused heterocycloalkenyl”, and “heteroarylfused heteroaryl”are similarly represented by the combination of the groups aryl,cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, andheteroaryl, as previously described. Any such groups may beunsubstituted or substituted with one or more ring system substituentsat any available position as described herein.

“Aralkyl” or “arylalkyl” means an aryl-alkyl-group in which the aryl andalkyl are as previously described. Preferred aralkyls comprise a loweralkyl group. Non-limiting examples of suitable aralkyl groups includebenzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parentmoiety is through the alkyl. The term (and similar terms) may be writtenas “arylalkyl-” to indicate the point of attachment to the parentmoiety.

Similarly, “heteroarylalkyl”, “cycloalkylalkyl”, “cycloalkenylalkyl”,“heterocycloalkylalkyl”, “heterocycloalkenylalkyl”, etc., mean aheteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, etc. as described herein bound to a parent moietythrough an alkyl group. Preferred groups contain a lower alkyl group.Such alkyl groups may be straight or branched, unsubstituted and/orsubstituted as described herein.

Similarly, “arylfused arylalkyl-”, arylfused cycloalkylalkyl-, etc.,means an arylfused aryl group, arylfused cycloalkyl group, etc. linkedto a parent moiety through an alkyl group. Preferred groups contain alower alkyl group. Such alkyl groups may be straight or branched,unsubstituted and/or substituted as described herein.

“Alkylaryl” means an alkyl-aryl-group in which the alkyl and aryl are aspreviously described. Preferred alkylaryls comprise a lower alkyl group.Non-limiting example of a suitable alkylaryl group is tolyl. The bond tothe parent moiety is through the aryl.

“Cycloalkylether” means a non-aromatic ring of 3 to 7 members comprisingan oxygen atom and 2 to 7 carbon atoms. Ring carbon atoms can besubstituted, provided that substituents adjacent to the ring oxygen donot include halo or substituents joined to the ring through an oxygen,nitrogen or sulfur atom.

“Cycloalkylalkyl” means a cycloalkyl moiety as defined above linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyl,adamantylpropyl, and the like.

“Cycloalkenylalkyl” means a cycloalkenyl moiety as defined above linkedvia an alkyl moiety (defined above) to a parent core. Non-limitingexamples of suitable cycloalkenylalkyls include cyclopentenylmethyl,cyclohexenylmethyl and the like.

“Heterocyclylalkyl” (or “heterocycloalkylalkyl”) means a heterocyclylmoiety as defined above linked via an alkyl moiety (defined above) to aparent core. Non-limiting examples of suitable heterocyclylalkylsinclude piperidinylmethyl, piperazinylmethyl and the like.

“Heterocyclenylalkyl” means a heterocyclenyl moiety as defined abovelinked via an alkyl moiety (defined above) to a parent core.

“Alkynylalkyl” means an alkynyl-alkyl-group in which the alkynyl andalkyl are as previously described. Preferred alkynylalkyls contain alower alkynyl and a lower alkyl group.

The bond to the parent moiety is through the alkyl. Non-limitingexamples of suitable alkynylalkyl groups include propargylmethyl.

“Heteroaralkyl” means a heteroaryl-alkyl-group in which the heteroaryland alkyl are as previously described. Preferred heteroaralkyls containa lower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude pyridylmethyl, 2-pyridinylmethyl, quinolinylmethyl, andquinolin-3-ylmethyl, and the like. The bond to the parent moiety isthrough the alkyl.

“Hydroxyalkyl” means a HO-alkyl-group in which alkyl is as previouslydefined. Preferred hydroxyalkyls contain lower alkyl. Non-limitingexamples of suitable hydroxyalkyl groups include hydroxymethyl and2-hydroxyethyl.

“Cyanoalkyl” means a NC-alkyl-group in which alkyl is as previouslydefined.

Preferred cyanoalkyls contain lower alkyl. Non-limiting examples ofsuitable cyanoalkyl groups include cyanomethyl and 2-cyanoethyl.

“Acyl” means an H—C(O)—, alkyl-C(O)— or cycloalkyl-C(O)—, group in whichthe various groups are as previously described. The bond to the parentmoiety is through the carbonyl. Preferred acyls contain a lower alkyl.Non-limiting examples of suitable acyl groups include formyl, acetyl andpropanoyl.

“Aroyl” means an aryl-C(O)— group in which the aryl group is aspreviously described. The bond to the parent moiety is through thecarbonyl. Non-limiting examples of suitable groups include benzoyl and1-naphthoyl.

“Heteroaroyl” means an heteroaryl-C(O)— group in which the heteroarylgroup is as previously described. The bond to the parent moiety isthrough the carbonyl. Non-limiting examples of suitable groups includepyridoyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond tothe parent moiety is through the ether oxygen.

“Alkyoxyalkyl” means a group derived from an alkoxy and alkyl as definedherein. The bond to the parent moiety is through the alkyl.

“Aryloxy” means an aryl-O— group in which the aryl group is aspreviously described. Non-limiting examples of suitable aryloxy groupsinclude phenoxy and naphthoxy. The bond to the parent moiety is throughthe ether oxygen.

“Aralkyloxy” (or “arylalkyloxy”) means an aralkyl-O— group (anarylaklyl-O— group) in which the aralkyl group is as previouslydescribed. Non-limiting examples of suitable aralkyloxy groups includebenzyloxy and 1- or 2-naphthalenemethoxy. The bond to the parent moietyis through the ether oxygen.

“Arylalkenyl” means a group derived from an aryl and alkenyl as definedherein. Preferred arylalkenyls are those wherein aryl is phenyl and thealkenyl consists of about 3 to about 6 atoms. The arylalkenyl can beoptionally substituted by one or more substituents. The bond to theparent moiety is through a non-aromatic carbon atom.

“Arylalkynyl” means a group derived from a aryl and alkenyl as definedherein. Preferred arylalkynyls are those wherein aryl is phenyl and thealkynyl consists of about 3 to about 6 atoms. The arylalkynyl can beoptionally substituted by one or more substituents. The bond to theparent moiety is through a non-aromatic carbon atom.

“Alkylthio” means an alkyl-S— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkylthio groupsinclude methylthio and ethylthio. The bond to the parent moiety isthrough the sulfur.

“Arylthio” means an aryl-S— group in which the aryl group is aspreviously described. Non-limiting examples of suitable arylthio groupsinclude phenylthio and naphthylthio. The bond to the parent moiety isthrough the sulfur.

“Aralkylthio” means an aralkyl-S— group in which the aralkyl group is aspreviously described. Non-limiting example of a suitable aralkylthiogroup is benzylthio. The bond to the parent moiety is through thesulfur.

“Alkoxycarbonyl” means an alkyl-O—CO— group. Non-limiting examples ofsuitable alkoxycarbonyl groups include methoxycarbonyl andethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

“Aryloxycarbonyl” means an aryl-O—C(O)— group. Non-limiting examples ofsuitable aryloxycarbonyl groups include phenoxycarbonyl andnaphthoxycarbonyl. The bond to the parent moiety is through thecarbonyl.

“Aralkoxycarbonyl” means an aralkyl-O—C(O)— group. Non-limiting exampleof a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond tothe parent moiety is through the carbonyl.

“Alkylsulfonyl” means an alkyl-S(O₂)— group. Preferred groups are thosein which the alkyl group is lower alkyl. The bond to the parent moietyis through the sulfonyl.

“Arylsulfonyl” means an aryl-S(O₂)— group. The bond to the parent moietyis through the sulfonyl.

“Spirocycloalkyl” means a cycloalkyl group attached to a parent moietyby replacement of two available hydrogen atoms at a single carbon atom.Non-limiting examples of spirocycloalkyl wherein the parent moiety is acycloalkyl include spiro [2.5] octane, spiro [2.4] heptane, etc. Themoiety may optionally be substituted as described herein. Non-limitingspirocycloalkyl groups include spirocyclopropyl, spriorcyclobutyl,spirocycloheptyl, and spirocyclohexyl.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound’ or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

Substitution on a cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl,heteroarylalkyl, arylfused cycloalkylalkyl-moiety or the like includessubstitution on any ring portion and/or on the alkyl portion of thegroup.

When a variable appears more than once in a group, e.g., R⁸ in —N(R⁵)₂,or a variable appears more than once in a structure presented herein,the variables can be the same or different.

With reference to the number of moieties (e.g., substituents, groups orrings) in a compound, unless otherwise defined, the phrases “one ormore” and “at least one” mean that there can be as many moieties aschemically permitted, and the determination of the maximum number ofsuch moieties is well within the knowledge of those skilled in the art.With respect to the compositions and methods comprising the use of “atleast one compound of the invention, e.g., of Formula (II),” one tothree compounds of the invention, e.g., of Formula (II) can beadministered at the same time, preferably one.

Compounds of the invention may contain one or more rings having one ormore ring system substituents. “Ring system substituent” means asubstituent attached to an aromatic or non-aromatic ring system which,for example, replaces an available hydrogen on the ring system. Ringsystem substituents may be the same or different, each being asdescribed herein or independently selected from the group consisting ofalkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, aryl, heteroaryl,aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl,alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl,aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio,cycloalkyl, heterocyclyl, —O—C(O)-alkyl, —O—C(O)-aryl,—O—C(O)-cycloalkyl, —C(═N—CN)—NH₂, —C(═NH)—NH₂, —C(═NH)—NH(alkyl),Y₁Y₂N—, Y₁Y₂N-alkyl-, Y₁Y₂NC(O)—, Y₁Y₂NSO₂— and —SO₂NY₁Y₂, wherein Y₁and Y₂ can be the same or different and are independently selected fromthe group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl.“Ring system substituent” may also mean a single moiety whichsimultaneously replaces two available hydrogens on two adjacent carbonatoms (one H on each carbon) on a ring system. Examples of such moietiesare rings such as heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl, and heterocycloalkenyl rings. Additional non-limitingexamples include methylene dioxy, ethylenedioxy, —C(CH₃)₂— and the likewhich form moieties such as, for example:

The line - as a bond generally indicates a mixture of, or either of, thepossible isomers, e.g., containing (R)- and (S)-stereochemistry. Forexample:

indicates a mixture of, or either of,

The wavy line

, as used herein, indicates a point of attachment to the rest of thecompound.

Lines drawn into the ring systems, such as, for example:

indicate that the indicated line (bond) may be attached to any of thesubstitutable ring carbon atoms.

“Oxo” is defined as a oxygen atom that is double bonded to a ring carbonin a cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, or otherring described herein, e.g.,

In this specification, where there are multiple oxygen and/or sulfuratoms in a ring system, there cannot be any adjacent oxygen and/orsulfur present in said ring system.

It is noted that the carbon atoms for compounds of the invention may bereplaced with 1 to 3 silicon atoms so long as all valency requirementsare satisfied.

As well known in the art, a bond drawn from a particular atom wherein nomoiety is depicted at the terminal end of the bond indicates a methylgroup bound through that bond to the atom, unless stated otherwise. Forexample:

represents

In the compounds of Formula (I)

The term “purified”, “in purified form” or “in isolated and purifiedform” for a compound refers to the physical state of said compound afterbeing isolated from a synthetic process (e.g. from a reaction mixture),or natural source or combination thereof. Thus, the term “purified”, “inpurified form” or “in isolated and purified form” for a compound refersto the physical state of said compound (or a tautomer or stereoisomerthereof, or pharmaceutically acceptable salt or solvate of saidcompound, said stereoisomer, or said tautomer) after being obtained froma purification process or processes described herein or well known tothe skilled artisan (e.g., chromatography, recrystallization and thelike), in sufficient purity to be suitable for in vivo or medicinal useand/or characterizable by standard analytical techniques describedherein or well known to the skilled artisan.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in organic Synthesis(1991), Wiley, New York.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. A discussion of prodrugs is provided in T. Higuchiand V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press. The term “prodrug” means a compound (e.g, a drugprecursor) that is transformed in vivo to yield a compound of theinvention or a pharmaceutically acceptable salt, hydrate or solvate ofthe compound. The transformation may occur by various mechanisms (e.g.,by metabolic or chemical processes), such as, for example, throughhydrolysis in blood. A discussion of the use of prodrugs is provided byT. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987.

For example, if a compound of the invention or a pharmaceuticallyacceptable salt, hydrate or solvate of the compound contains acarboxylic acid functional group, a prodrug can comprise an ester formedby the replacement of the hydrogen atom of the acid group with a groupsuch as, for example, (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl,1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di (C₁-C₂)alkylcarbamoyl-(C1-C2)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a compound of the invention contains an alcohol functionalgroup, a prodrug can be formed by the replacement of the hydrogen atomof the alcohol group with a group such as, for example,(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate),and the like.

If a compound of the invention incorporates an amine functional group, aprodrug can be formed by the replacement of a hydrogen atom in the aminegroup with a group such as, for example, R-carbonyl, RO-carbonyl,NRR′-carbonyl where R and R′ are each independently (C₁-C₁₀)alkyl,(C₃-C₇) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl ornatural α-aminoacyl, —C(OH)C(O)OY¹ wherein Y¹ is H, (C₁-C₆)alkyl orbenzyl, —C(OY²)Y³ wherein Y² is (C₁-C₄) alkyl and Y³ is (C₁-C₆)alkyl,carboxy (C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N— ordi-N,N—(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵ wherein Y⁴ is H or methyl and Y⁵is mono-N— or di-N,N—(C₁-C₆)alkylamino morpholino, piperidin-1-yl orpyrrolidin-1-yl, and the like.

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. “Solvate” means a physicalassociation of a compound of this invention with one or more solventmolecules. This physical association involves varying degrees of ionicand covalent bonding, including hydrogen bonding. In certain instancesthe solvate will be capable of isolation, for example when one or moresolvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Non-limiting examples of suitable solvates includeethanolates, methanolates, and the like. “Hydrate” is a solvate whereinthe solvent molecule is H₂O.

One or more compounds of the invention may optionally be converted to asolvate. Preparation of solvates is generally known. Thus, for example,M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describethe preparation of the solvates of the antifungal fluconazole in ethylacetate as well as from water. Similar preparations of solvates,hemisolvate, hydrates and the like are described by E. C. van Tonder etal, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham etal, Chem. Commun., 603-604 (2001). A typical, non-limiting, processinvolves dissolving the inventive compound in desired amounts of thedesired solvent (organic or water or mixtures thereof) at a higher thanambient temperature, and cooling the solution at a rate sufficient toform crystals which are then isolated by standard methods. Analyticaltechniques such as, for example I. R. spectroscopy, show the presence ofthe solvent (or water) in the crystals as a solvate (or hydrate).

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective in inhibiting the above-noted diseases and thus producing thedesired therapeutic, ameliorative, inhibitory or preventative effect.

The compounds of the invention can form salts which are also within thescope of this invention. Reference to a compound of the invention hereinis understood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof the invention contains both a basic moiety, such as, but not limitedto a pyridine or imidazole, and an acidic moiety, such as, but notlimited to a carboxylic acid, zwitterions (“inner salts”) may be formedand are included within the term “salt(s)” as used herein.Pharmaceutically acceptable (i.e., non-toxic, physiologicallyacceptable) salts are preferred, although other salts are also useful.Salts of the compounds of the invention may be formed, for example, byreacting a compound of the invention with an amount of acid or base,such as an equivalent amount, in a medium such as one in which the saltprecipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates,) and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook ofPharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(I) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g. decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g. benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Pharmaceutically acceptable esters of the present compounds include thefollowing groups: (1) carboxylic acid esters obtained by esterificationof the hydroxy groups, in which the non-carbonyl moiety of thecarboxylic acid portion of the ester grouping is selected from straightor branched chain alkyl (for example, acetyl, n-propyl, t-butyl, orn-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (forexample, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (forexample, phenyl optionally substituted with, for example, halogen,C₁₋₄alkyl, or C₁₋₄alkoxy or amino); (2) sulfonate esters, such as alkyl-or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters(for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5)mono-, di- or triphosphate esters. The phosphate esters may be furtheresterified by, for example, a C₁₋₂₀ alcohol or reactive derivativethereof, or by a 2,3-di (C₆₋₂₄)acyl glycerol.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers. Also,some of the compounds of the invention may be atropisomers (e.g.,substituted biaryls) and are considered as part of this invention.Enantiomers can also be separated by use of chiral HPLC column.

It is also possible that the compounds of the invention may exist indifferent tautomeric forms, and all such forms are embraced within thescope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.Thus, for example, the compounds of the invention conforming to theformula:

and their tautomers:

are both contemplated as being within the scope of the compounds of theinvention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, esters and prodrugs of the compounds as well as the salts,solvates and esters of the prodrugs), such as those which may exist dueto asymmetric carbons on various substituents, including enantiomericforms (which may exist even in the absence of asymmetric carbons),rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this invention, as are positionalisomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example,if a compound of the invention incorporates a double bond or a fusedring, both the cis- and trans-forms, as well as mixtures, are embracedwithin the scope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.).

Individual stereoisomers of the compounds of the invention may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, isintended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

The present invention also embraces isotopically-labelled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.

Certain isotopically-labelled compounds of the invention (e.g., thoselabeled with ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H or D) may afford certain therapeutic advantagesresulting from greater metabolic stability (e.g., increased in vivohalf-life or reduced dosage requirements) and hence may be preferred insome circumstances. Isotopically labelled compounds of the invention cangenerally be prepared by following procedures analogous to thosedisclosed in the Schemes and/or in the Examples hereinbelow, bysubstituting an appropriate isotopically labelled reagent for anon-isotopically labelled reagent. Non-limiting examples of deuteratedcompounds of the invention are described hereinbelow.

Polymorphic forms of the compounds of the invention, and of the salts,solvates, esters and prodrugs of the compounds of the invention, areintended to be included in the present invention.

Suitable doses for administering compounds of the invention to patientsmay readily be determined by those skilled in the art, e.g., by anattending physician, pharmacist, or other skilled worker, and may varyaccording to patient health, age, weight, frequency of administration,use with other active ingredients, and/or indication for which thecompounds are administered. Doses may range from about 0.001 to 500mg/kg of body weight/day of the compound of the invention. In oneembodiment, the dosage is from about 0.01 to about 25 mg/kg of bodyweight/day of a compound of the invention, or a pharmaceuticallyacceptable salt or solvate of said compound. In another embodiment, thequantity of active compound in a unit dose of preparation may be variedor adjusted from about 1 mg to about 100 mg, preferably from about 1 mgto about 50 mg, more preferably from about 1 mg to about 25 mg,according to the particular application. In another embodiment, atypical recommended daily dosage regimen for oral administration canrange from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to200 mg/day, in two to four divided doses.

As discussed above, the amount and frequency of administration of thecompounds of the invention and/or the pharmaceutically acceptable saltsthereof will be regulated according to the judgment of the attendingclinician considering such factors as age, condition and size of thepatient as well as severity of the symptoms being treated.

When used in combination with one or more additional therapeutic agents,the compounds of this invention may be administered together orsequentially. When administered sequentially, compounds of the inventionmay be administered before or after the one or more additionaltherapeutic agents, as determined by those skilled in the art or patientpreference.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described herein andthe other pharmaceutically active agent or treatment within its dosagerange.

Accordingly, in an aspect, this invention includes combinationscomprising an amount of at least one compound of the invention, or apharmaceutically acceptable salt, solvate, ester or prodrug thereof, andan effective amount of one or more additional agents described above.

The pharmacological properties of the compounds of this invention may beconfirmed by a number of pharmacological assays. Certain assays areexemplified elsewhere in this document.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.,magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18^(th) Edition, (1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

The compounds of this invention may also be delivered subcutaneously.

In one embodiment, the compound is administered orally.

In some embodiments, it may be advantageous for the pharmaceuticalpreparation comprising one or more compounds of the invention beprepared in a unit dosage form. In such forms, the preparation issubdivided into suitably sized unit doses containing appropriatequantities of the active component, e.g., an effective amount to achievethe desired purpose.

PREPARATIVE EXAMPLES

Compounds of the invention can be made using procedures known in theart. The following reaction schemes show typical procedures, but thoseskilled in the art will recognize that other procedures can also besuitable.

Techniques, solvents and reagents may be referred to by their followingabbreviations:

Thin layer chromatography: TLC High performance liquid chromatography:HPLC ethyl acetate: AcOEt or EtOAc methanol: MeOH ether or diethylether: Et₂O tetrahydrofuran: THF Acetonitrile: MeCN or ACN1,2-dimethoxyethane: DME Trifluoroacetic acid: TFA Dimethylacetamide:DMA Dimethylformamide: DMF Dimethylsulfoxide: DMSO triethylamine: Et₃Nor TEA tert-Butoxycarbonyl: t-Boc or Boc2-(Trimethylsilyl)ethoxycarbonyl: Teoc liquid chromatography massspectrometry: LCMS milliliters: mL millimoles: mmol micromoles: μmolmicroliters: μl grams: g milligrams: mg N-iodosuccinimide: NIS roomtemperature (ambient, about 25° C.): rt (or RT) Retention time: t_(R)N-bromosuccinimide: NBS Methyl magnesium bromide: MeMgBr iron(III)acetylacetonate: Fe(acac)₃ Diphenylphosphoryl azide: DPPA1-(3-Dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride: EDCIDiisopropylethylamine: DIEA or iPr₂NEt Diisopropylamine: iPr₂NH2-(Trimethylsilyl)ethanol: TMSethanol 3-Chloroperoxybenzoic acid: mCPBAn-Butyllithium: nBuLi lithium diisopropylamide: LDA[1,1′Bis(diphenylphosphino)ferrocene]di- chloropalladium(II): PdCl₂dppfPalladium(II) acetate: Pd(OAc)₂ Methanesulfonyl chloride: MeSO₂ClBenzyl: Bn 4-methoxy benzyl: PMB Phenyl: Ph Ethanol: EtOH Liter: LMinutes: min Reverse phase: RP Hexanes: Hex Methylene Chloride: DCMAcetic acid: HOAc or AcOH Saturated: Sat (or sat)Bis(2-oxo-3-oxazolidinyl) phosphinic chloride: BOPCl4-(dimethylamino)pyridine: DMAP Molar: M2-((trimethylsilyl)ethoxy)methyl: SEM Diisopropyl azodicarboxylate: DIADTriethylborane: Et₃B Tris(dibenzylideneacetone)dipalladium(0): Pd₂dba₃Pyridine: Pyr (2-Biphenyl)di-tert-butylphosphine: John-Phos2-dicyclohexylphosphino-2′,4′,6′- triisopropyl biphenyl: X-Phos2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3- tetramethyl uroniumhexafluorophosphate: HATU Concentrated: conc. Tetrabutyl ammoniumfluoride: TBAF 2-Dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl: RuPhosTetrakis(triphenylphosphine)palladium: Pd(PPh₃)₄

Step 1:

To a solution of 2,4-difloroacetophenone (15.0 g, 96 mmol) in THF (100mL) was added (R)-2-methyl-2-propanesulfinamide (12.8 g, 106 mmol) andTi(OEt)₄, (32.0 g, 120 mmol). The resultant solution was heated toreflux overnight. After that time, the solution was cooled to RT andpoured onto ice. To this mixture was added CH₂Cl₂ and the resultantmixture was stirred at RT for 10 min. The mixture was then filteredthrough Celite. The filter cake was washed with CH₂Cl₂. The layers wereseparated. The aqueous layer was extracted with CH₂Cl₂ (2×). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated. The crude product was purified via flash chromatography(SiO₂:gradient elution 100:0 to 45:55 hexanes:EtOAc) to afford theketimine (12.3 g).

Step 2:

To a stirred solution of 4-methoxybenzyl amine (198.9 g, 1.45 mol) inanhydrous pyridine (400 mL) at 0° C. was added dropwise via an additionfunnel methanesulfonyl chloride (116 mL, 1.45 mol) over 45 min. Afterthe addition was complete, the cooling bath was removed and theresultant solution was stirred at RT overnight. The reaction wasconcentrated in vacuo (water bath 60-65° C.) to remove most of thepyridine. The residue was taken up in CH₂Cl₂(1 L). The organic solutionwas washed with 1 N HCl_((aq.))(2×1 L), sat. NaHCO₃ (aq) (2×1 L) andbrine (1×500 mL). The organic layer was dried over Na₂SO₄, filtered andconcentrated to afford a crude solid. This solid was dissolved in 95%EtOH (430 mL) using a steam bath to warm the solution. The solution wasallowed to cool, causing the product to precipitate from solution. Theproduct was removed by filtration and the solid was washed with coldEtOH (3×150 mL). A second crop was obtained after allowing the motherliquor to stir at RT overnight. The overall yield of the product was246.5 g (79% yield).

This product was dissolved in anhydrous DMF (3.0 L), cooled to 0° C. andplaced under an atmosphere of N₂. To this solution was added in smallportions sodium hydride (60% in mineral oil, 60.2 g, 1.51 mol, 1.3 eq.).After the addition was complete, the mixture was stirred for anadditional 10 min. To this mixture was added dropwise via an additionfunnel methyl iodide (250 g, 1.76 mol, 1.5 eq.). After the addition wascomplete, the cooling bath was removed and the mixture was allowed tostir at RT overnight. The mixture was then concentrated in vacuo (p=10torr, bath temp=55-60° C.) to remove ca. 2.5 L of DMF. Some solidsprecipitated from the solution. The remaining mixture was partitionedbetween 5 L ice water, 5 L Et₂O and 500 mL of EtOAc. The organic layerwas separated. The aqueous layer was extracted with Et₂O (2×1 L). Thecombined organic layers were washed with brine (2×1 L), dried overNa₂SO₄, filtered and concentrated. The solid was stirred with hexanesusing a wire stir blade to powderize the solid. The solid was removed byfiltration and washed with hexanes (2×250 mL). The solid was dissolvedin hexanes/EtOAc (1:1, 450 mL) using a steam bath to warm the mixture.An off white precipitate formed on cooling and was filtered off (182 g).The remaining mother liquor was purified via flash chromatography(SiO₂:1:1 hexanes:EtOAc) to afford additional product (51.8 g) for anoverall yield of 233.8 g (89% yield).

Step 3:

To a solution of the sulfonamide from step 2 (4.18 g, 18.2 mmol) inanhydrous THF (50 mL) at −78° C. under an atmosphere of N₂ was addeddropwise a solution of n-BuLi (1.6 M in hexanes, 11.4 mL, 18.2 mmol).The resultant solution was stirred at −78° C. for 30 min. After thattime, a solution of the ketimine from step 1 (3.15 g, 12.1 mmol) in THF(50 mL) precooled to −78° C. in a separate round bottom flask wastransferred via cannula to the solution above. The resultant solutionwas stirred at −78° C. for 3.5 hours. Water was added and the mixturewas allowed to warm to RT. The aqueous layer was extracted with EtOAc(3×). The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated. The crude product was purified viaflash chromatography (SiO₂:gradient elution 100:0 to 40:60hexanes:EtOAc) to afford the sulfinamide (3.95 g, 67% yield).

Step 4:

To a solution of the sulfinamide from step 3 (3.80 g, 7.6 mmol) inCH₂Cl₂/MeOH (3:1 80 mL) was added a solution of 4 M HCl_((dioxane))(11.4 mL, 45.4 mmol). The resultant solution was stirred at RT for 1.5hours. The solution was concentrated. The residue was re-concentratedfrom toluene (1×). The residue was then taken up in CHCl₃ and TFA (26mL, 1:1). To this solution was added 1,3-dimethoxybenzene (6.5 mL, 50mmol). The resultant solution was stirred at RT overnight. The resultantsolution was concentrated. The resultant oil was partitioned betweenEt₂O and 1 M HCl_((aq.)). The aqueous layer was extracted with Et₂O(2×). The aqueous layer was then adjusted to pH 10 with the addition ofsat. Na₂CO_(3 (aq.)). The aqueous layer was extracted with CH₂Cl₂ (3×).The organic layers were extracted from the basic aqueous layer,combined, dried over Na₂SO₄, filtered and concentrated to afford theamine (1.88 g, 85%).

Step 5:

To a solution of the amine from step 4 (1.80 g, 6.8 mmol) in CH₂Cl₂ (30mL) was added benzoyl isothiocyanate (1.01 mL, 7.49 mmol). The resultantsolution was stirred at RT overnight. The solution was thenconcentrated. The residue was redissolved in MeOH (20 mL). To thissolution was added a solution of NaOMe in MeOH (25%, 3.9 mL). Theresultant solution was stirred at RT for 45 min. The solution wasconcentrated in vacuo. The residue was then partitioned between CH₂Cl₂and water. The pH of the aqueous layer was adjusted to ca 11 with theaddition of NaHCO₃ (aq.). The aqueous layer was extracted with CH₂Cl₂(3×). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated to afford the thiourea (1.90 g, 86%).

Step 6:

To the thiourea from step 5 (1.90 g, 5.88 mmol) in EtOH (40 mL) wasadded methyl iodide (0.42 mL, 6.7 mmol). The resultant solution washeated to reflux for 3 hours. The solution was cooled to RT andconcentrated in vacuo. The residue was partitioned between EtOAc andNa₂CO₃ (aq.). The aqueous layer was extracted with EtOAc (3×). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated. The crude product was purified via flashchromatography (SiO₂:gradient elution 100:0 to 92:8 CH₂Cl₂:MeOH) toafford Ex. 1 (1.12 g, 66% yield). LCMS (conditions D): t_(R)=1.73 min,m/e=290.2 (M+H).

TABLE I The following sulfonamides were prepared using a proceduresimilar to that described in Scheme 1a step 2. Entry Amine Alkyl halidesulfonamide 1 

2 

3*

CD₃I

4*

*Cesium carbonate was used as the base instead of NaH for entries 3 and4.

Step 1:

To a mixture of Ex. 1. (8.00 g, 28.0 mmol) and concentrated sulfuricacid (16 mL) was added fuming nitric acid (2.24 mL) at 0° C. Thereaction mixture was stirred from 0° C. to room temperature over 2 h.After this time, the reaction mixture was basified with sodium carbonateto pH 10 and extracted with ethyl acetate (2×200 mL). The combinedextracts were dried over anhydrous Na₂SO₄, filtered, and concentratedunder reduced pressure to afford the nitro compound (8.81 g, 94%).

Step 1:

To a solution of 3-trifluoromethyl thiophene (3.75 g, 24.6 mmol) inanhydrous THF (60 mL) at −78° C. was added a solution of n-BuLi (2.5 Min hexanes, 13 mL, 32.5 mmol). The resultant solution was stirred at−78° C. for 10 min. To the solution was bubbled CO_(2 (g)) for 20 min at−78° C. The solution was allowed to warm to RT and stirred for anadditional 40 min at RT while bubbling of CO_(2 (g)) through thesolution was continued. After that time, 1 M HCl_((aq.)) was added tothe solution. The aqueous layer was then extracted with EtOAc. Theorganic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated. The crude product was purified via flash chromatography(SiO₂:85:15:1 CH₂Cl₂:MeOH:AcOH) to afford the carboxylic acid (4.33 g,90%).

Step 2:

To a solution of a portion of the acid from step 1 (465 mg, 2.37 mmol)in CH₂Cl₂ (12 mL) and DMF (0.20 mL) at 0° C. was added dropwise asolution of oxalyl chloride (2 M in CH₂Cl₂, 3.5 mL, 3 eq.). Theresultant solution was stirred at 0° C. for 15 min followed by anadditional 1 hour at RT. The solution was concentrated. To the residuewas added N,O-dimethylhydroxylamine hydrochloride (470 mg, 2 eq.)followed by CH₂Cl₂ (18 mL). The resultant mixture was cooled to 0° C. Tothis mixture was added Et₃N (1.4 mL) and DMAP (10 mg). The solution wasstirred at 0° C. for 1 hour. To the solution was added 1 M HCl_((aq.))(60 mL) and CH₂Cl₂ (60 mL). The layers were separated. The organic layerwas washed with brine, dried and concentrated. The crude residue waspurified via flash chromatography (SiO₂:gradient elution 100:0 to 60:40heptane:EtOAc) to afford the amide (426 mg, 75%).

Step 3:

To a solution of the amide from step 2 (4.10 g, 17.1 mmol) in THF (70mL) at 0° C. was slowly added a solution of methyl magnesium bromide (3M in Et₂O, 7 mL). The resultant solution was stirred at 0° C. for 3hours. After that time, 1 M HCl_((aq.)) was added. The mixture was thenextracted with Et₂O. The organic layer was dried, filtered andconcentrated. The residue was purified via flash chromatography(SiO₂:gradient elution 100:0 to 60:40 pentane:EtOAc) to afford theketone (3.22 g, 97%) as a colorless oil.

TABLE Ib The following ketones were prepared using similar procedures tothat described in Scheme 2, Steps 2 and 3 using the appropriatecarboxylic acids.

Step 1:

To a solution of 6-bromo-3-chloropicolinaldehyde (10.0 g, 45.45 mmol) in200 mL THF stirring at −78° C. under N₂ was slowly added methylmagnesiumbromide (3.0 M in diethyl ether, 16.63 mL, 50 mmol). The reaction wasstirred at this temperature for 3 hours, and then saturated ammoniumchloride was added. The mixture was extracted with EtOAc. The combinedorganic layers were dried (MgSO₄), filtered, and concentrated in vacuo.The residue was purified by silica gel chromatography (0-10%EtOAc/hexanes over 20 minutes) to provide1-(6-bromo-3-chloropyridin-2-yl)ethanol (8.4 g, 78%).

Step 2:

The material prepared above (8.4 g, 35.5 mmol) was stirred overnight atroom temperature in 100 mL DCM along with pyridinium chlorochromate (15g, 71 mmol) and approximately 5 g celite. The reaction was filteredthrough celite and washed with DCM. The filtrate was concentrated todryness in vacuo and the residue was purified by silica gelchromatography (0-10% EtOAc/hexanes over 22 minutes) to provide1-(6-bromo-3-chloropyridin-2-yl)ethanone (6.85 g, 82%).

TABLE Ic The following ketone was made using methods similar to thosedescribed in Scheme 2b: Entry Aldehyde Ketone 1

Step 1:

To a solution of 2-chloro-3-fluorobenzoic acid (30 g, 172 mmol) in 300mL of DCM was added carbonyldiimidazole (CDI) (32.0 g, 198 mmol) inportions. After addition and then stirring at RT for 1 h,N,O-dimethylhydroxylamine HCl salt (18.5 g, 189 mmol) was added into themixture followed by Et₃N (20 mL). The mixture was stirred at RTovernight. After the reaction was quenched with water, the aqueous layerwas extracted with DCM (2×). The organic layers were washed with 2N HCl(aq), water, sat. NaHCO₃ (aq) and brine. The solution was dried (MgSO₄)and concentrated. The product2-chloro-3-fluoro-N-methoxy-N-methylbenzamide (32.0 g) was obtained bysilica gel chromatography (elution with 0-30% EtOAc/Hex).

Step 2:

The above material was treated according to Scheme 2, Step 3 to providethe ketone product (89% yield).

TABLE II The following examples were prepared using similar proceduresto that described in Scheme 1a using the appropriate starting materials.Examples (LCMS data listed with each compound: observed MH⁺, HPLCretention time and LCMS method)

2 MH⁺: 308.2, 1.64 min, D

3 MH⁺: 290.0, 1.99 min, B

4 MH⁺: 294.2, 1.43 min, A

5 MH⁺: 340.2, 2.64 min, A

6 MH⁺: 331.9, 1.95 min, B

7 MH⁺: 340.2, 2.19 min, A

8

9

10

11 MH⁺: 339.8, 1.87 min, A

12 MH⁺: 278.9, 1.73 min, B

13 MH⁺: 285.0, 1.54 min, B

14 MH⁺: 340.2, 2.44 min, A

14a MH⁺: 350.0, 1.72 min, D

14b

14c

14d

To a solution of Ex. 5 (1.60 g, 5.53 mmol) in CH₂Cl₂ was added Boc₂O(1.24 g, 5.68 mmol) and Et₃N (0.82 mL, 5.91 mmol). The resultantsolution was stirred at RT overnight. The solution was washed with ½saturated NaHCO_(3 (aq.)). The aqueous layer was back extracted withCH₂Cl₂ (2×). The combined organic layers were dried over Na₂SO₄,filtered and concentrated. The crude product was purified via flashchromatography (SiO₂:gradient elution 100:0 to 70:30 hexanes:EtOAc) toafford the tert-butyl carbamate (1.74 g, 84% yield).

TABLE IIb The following carbamates were prepared using similarprocedures to that described in Scheme 3 using the appropriate startingmaterials. Entries

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

TABLE IIc The following example was prepared using a procedure similarto that described in Scheme 1b, using the following modified temperatureprofile: nitric acid addition at −40 degrees C., then warming to 0degrees C. Ex- ample Starting material Product 14e

Example 14d

TABLE IId The following thiadiazine dioxides were made according tomethods similar to those in Schemes 1a and 3, with the noted exceptions:Entries

1^(a,b)

2^(a,b)

3^(c)

Ex. 14f^(d,e) ^(a)(S)-2-Methyl-2-propanesulfinamide was used in Step 1Scheme 1a instead of (R)-2-methyl-2-propanesulfinamide.^(b)Re-crystallization from 95% MeOH/5% water was used to remove adiastereomeric product after silica gel purification in Step 3 Scheme1a. ^(c)SFC chromatography (TharSFC80, Chiralpak OD-H, 50 × 250 mm, 5μm, 150 bar with 30% iPrOH, 250 g/min, 40° C.) used to remove adiastereomeric product after silica gel purification in Step 3 Scheme1a. ^(d)SFC chromatography (TharSFC80, Chiralpak OJ-H, 50 × 250 mm, 5μm, 150 bar with 25% iPrOH, 250 g/min, 40° C.) used to remove adiastereomeric product after silica gel purification in Step 3 Scheme1a. ^(e)The product of Scheme 1a Step 4 was treated according to Scheme3b to afford Example 14f directly, instead of employing Scheme 1a, Steps5 and 6.

Steps 1-4:

These steps were performed using similar procedures to those describedin steps 1-4 of Scheme 1a.

Step 5:

To a solution of the amine from step 4 (10.5 g, 36 mmol) in CH₂Cl₂ (200mL) was added benzoylisothiocyanate (4.3 mL, 1.1 eq.). The resultingsolution was stirred at RT for 2.5 days. Additionalbenzoylisothiocyanate (0.86 mL, 0.2 eq.) was added and the solution wasstirred at RT for an additional 2 hours. The solution was thenconcentrated in vacuo.

A portion of this material (6.5 g, ˜14 mmol) was dissolved in MeOH (200mL). To this solution was added Na₂CO_(3 (s)) (1.52 g, 14 mmol). Theresultant mixture was stirred at RT for 45 min. After that time, aslight excess of HOAc was added to the solution. The mixture was thenconcentrated. The residue was partitioned between CH₂Cl₂ and ½ sat.NaHCO_(3 (aq.)). The aqueous layer was extracted with CH₂Cl₂ (3×). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated. The thiourea (˜4.9 g) was carried onto the next reactionwithout further purification.

Step 6:

Example 15 was prepared using a method similar to that described inScheme 1a step 6.

To a slurry of amine A (Scheme 3a step 4) (13.7 grams) in n-butanol (150mL) was added a solution of cyanogen bromide (5M in MeCN). The resultantmixture was heated to reflux for 4 hours. The mixture was concentratedto ⅓ of the original volume, To the mixture was added Et₂O (200 mL). Theresultant solid was removed via filtration and the solid was washed withEt₂O (2×). The solid was partitioned between EtOAc and sat. Na₂CO₃(aq.). The aqueous layer was extracted with EtOAc (3×). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated to afford 10.6 grams of Ex. 15. This material was convertedto the t-butyl carbamate using a procedure similar to that described inScheme 3.

TABLE IIe The following thiadiazine dioxides were prepared usingprocedures similar to those described in Schemes 3a (entry 1), 3b(entries 2-5) and 3 using the sulfonamides shown in Table I and Scheme1a. Entries

1

2

3

4

5

To a solution of Ex. 2 (3.8 g, 12.2 mmol) in MeCN (40 mL) was added4-methoxybenzyl chloride (4.6 g, 29 mmol), Cs₂CO₃ (9.9 g, 31 mmol) andn-Bu₄NI (450 mg, 1.2 mmol). The resultant mixture was heated to refluxfor 16 hours. After that time, additional 4-methoxybenzyl chloride (1.9g, 12 mmol) and Cs₂CO₃ (4.4 g, 12 mmol) were added and the mixture washeated to reflux for an additional 4 hours. The mixture was thenconcentrated in vacuo at RT. The residue was partitioned between waterand CH₂Cl₂. The aqueous layer was extracted with CH₂Cl₂. The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated. Thecrude residue was purified via flash chromatography (SiO₂:gradientelution 100:0 to 80:20 hexanes:EtOAc) to afford the bis-PMB compound A(4.9 g, 73%).

A 20 mL microwave vessel was flame-dried and cooled under vacuum, thenbackfilled with N₂, followed by two cycles of vacuum/N₂ backfill. NaHMDS(1 M in THF, 2.2 mL, 2.2 mmol) was added to a solution of thiadiazinedioxide A ((Scheme 4) 547 mg, 1.0 mmol) in dioxane (5 mL) at RT, andstirred for 30 min. A freshly prepared solution of ZnCl₂ (1.2 M in THF,2.0 mL, 2.4 mmol) was added, and stirring continued for 30 min at RT.Pd(OAc)₂ (45 mg, 0.2 mmol), X-Phos (190 mg, 0.4 mmol) and arylbromide B(509 mg 1.80 mmol) were added and the reaction mixture was degassed (4×vacuum/N₂), capped and placed into a preheated 100° C. oil bath for 3 h.The crude reaction was cooled to RT, diluted with EtOAc/water, filteredthrough a pad of celite, and the aqueous layer extracted with EtOAc(2×). The combined organic layers were washed with brine (1×), driedover Na₂SO₄, filtered and concentrated under reduced pressure to give acrude residue that was subjected to silica gel chromatography (0→30%EtOAc/hexanes) followed by RP-HPLC conditions (monitoring at 220 nm) togive intermediate C (73 mg, 97 umol).

A solution of intermediate C (73 mg, 97 umol) in CH₃CN (4 mL) was heatedto 75° C., and a solution of K₂HPO₄ (26 mg, 147 umol), KH₂PO₄ (20 mg,147 umol) and K₂S₂O₈ (158 mg, 588 umol) in water (2 mL) was added viapipette. After 60 min at 75° C., the reaction mixture was cooled to RTand concentrated under vacuum. The residue was subjected to RP-HPLCconditions to give Ex. 16 (TFA salt, 26 mg). LCMS data: (method D):t_(R)=2.17 min, m/e=510.0 (M+H).

Sodium hydride (60% in oil, 1.5 g, 37.5 mmol) was added to a solution of5-bromoindazole D (6 g, 30.6 mmol) in DMF (60 mL) at RT. After stirringfor 30 min, methyl iodide (2.83 mL, 45.9 mmol) was added and thereaction stirred for another 2 h at RT. The reaction was quenched withsat. NaHCO₃ (aq), extracted with EtOAc (1×), dried over MgSO₄, filtered,and concentrated under reduced pressure to give a mixture of N-1 and N-2methylated 5-bromoindazoles E and F, which were separated by silica-gelchromatography using 0→30% EtOAc/hexanes.

Example 17 was prepared as described for Example 16 in Scheme 5,substituting arylbromide E for B. LCMS data: (method C): t_(R)=3.12 min,m/e=438.2 (M+H).

Steps 1-4:

These steps were performed using similar procedures to those describedin steps 1-4 of Scheme 1a.

Step 5:

This step was performed using a procedure similar to that described inScheme 3b except t-BuOH was used as the solvent instead of n-BuOH.

Step 6:

The t-butyl carbamate was installed using a procedure similar to thatdescribed in Scheme 3.

Step 7:

A mixture of the bromide (3.00 g, 6.92 mmol), benzophenone imine (1.39mL, 8.30 mmol), Pd₂(dba)₃ (0.634 g, 0.692 mmol), John-Phos (0.413 g,1.38 mmol), sodium tert-butoxide (2.13 g, 22.1 mmol), and toluene (51mL) was degassed (vacuum/N₂). The mixture was then stirred at 65° C.under nitrogen for 3 h. After this time, the reaction mixture was cooledto room temperature and filtered through a pad of Celite and rinsed withethyl acetate (100 mL). The filtrate was concentrated under reducedpressure. The residue was then dissolved in methanol (76 mL) and theresulting solution was charged with hydroxyl amine hydrochloride (2.16g, 31.1 mmol) and sodium acetate (2.55 g, 31.1 mmol). The reactionmixture was stirred at room temperature for 40 min. After this time, thereaction mixture was concentrated under reduced pressure. The resultingresidue was dissolved in ethyl acetate (200 mL) and washed withsaturated aqueous sodium bicarbonate (100 mL), water (100 mL), and brine(100 mL). The organic layer was then dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by column chromatography (silica, 0-100% ethylacetate/heptane) to afford the amino pyridine (0.880 g, 34%).

To a flame-dried flask was added a pyridyl bromide (Table IIb, Entry 15,1.5 g, 3.3 mmol), Pd₂(dba)₃ (305 mg, 0.3 mmol),(2-biphenyl)di-tert-butylphosphine (200 mg, 0.7 mmol), sodiumtert-butoxide (1.02 g, 0.011 mmol), benzophenone imine (670 ul, 4 mmol),and toluene (21 mL). The mixture was evacuated under vacuum andback-filled with N₂ (3×). The mixture was stirred at 60° C. for 1 h.After filtration through celite, the filtrate was concentrated. Thecrude residue was dissolved in 36 mL of methanol, and hydroxyl aminehydrochloride (458 mg, 6.6 mmol) and sodium acetate (541 mg, 6.6 mmol)were added. The reaction was stirred for 35 min and then quenched withsaturated aqueous sodium bicarbonate. The mixture was extracted withethyl acetate, and the combined organic portions were dried overmagnesium sulfate and concentrated. The crude residue was purified by aflash silica column (50% ethyl acetate/hexane) to get an aminopyridineproduct (730 mg, 68%).

TABLE IIIa The following amino-pyridines were prepared using similarprocedures to those described in Scheme 7a using the appropriate ketonesfrom Table Ib. Entries

1

2

3

TABLE IIIb The following compound was prepared from the bromide (TableIIb entry 16) using methods similar to those described in Scheme 7b:

To a solution of a halophenyl thiadiazine (Table IId, entry 1: 2.31 g,5.9 mmol) in 5 mL of DCM was added 1 mL of TFA. The mixture was stirredfor 4 h and then concentrated. At 0° C., to a solution of this cruderesidue in 4 mL of sulfuric acid was carefully added a mixture of 0.5 mLof fuming nitric acid and 1.2 mL of sulfuric acid. The mixture wasstirred at 0° C. for 2 h and then poured into 150 mL of ice. The mixturewas neutralized by carefully adding saturated sodium bicarbonatesolution and solid sodium hydroxide. The resulting mixture was extractedwith ethyl acetate, and the combined organic layers were dried overmagnesium sulfate and concentrated. This crude residue was dissolved in20 mL of DCM, and (Boc)₂O (1.29 g, 5.9 mmol), and DIEA (2.56 mL, 14.75mmol) were added. The reaction was stirred overnight, and then quenchedwith 1N HCl. The mixture was extracted with DCM, the organic portionswere combined, dried over magnesium sulfate, and concentrated. The cruderesidue was purified by a flash silica column (25% ethyl acetate/hexane)to give a nitrophenyl thiadiazine product (1.93 g, 76% yield).

TABLE IIIc The following compounds were made using methods similar tothose described in Scheme 7c starting from the appropriate startingmaterials shown in Table IIb: Entries

1

2

3

4

TABLE IIId The following compound was made from Ex. 14f using methodssimilar to those described in Scheme 7c, omitting the initial treatmentwith TFA:

To a solution of N-(4-methoxybenzyl)-N-methylmethanesulfonamide (26.8 g,117 mmol) in THF (200 mL) at −78° C. was added n-butyllithium (2.5 M inhexanes, 47 mL, 118 mmol) over 10 minutes. After the addition wascomplete, the mixture was allowed to stir at −78° C. for 1 h.

To this mixture was then added a solution of(S)-2-methyl-N-(1-(2,4,6-trifluorophenyl)ethylidene)propane-2-sulfinamide(21.6 g, 77.9 mmol, prepared from 2,4,6-trifloroacetophenone and(S)-2-methyl-2-propanesulfinamide according to Scheme 1a, Step 1) in THF(150 mL) at −78° C. The resulting mixture was allowed to stir at −78° C.for 4 h. At that time, the reaction was quenched by rapid dilution withwater (˜400 mL). The mixture was then warmed to RT, further diluted withEtOAc and brine. The phases were separated, and the aqueous layer wasextracted with EtOAc (4×). The organic portions were combined, washedwith brine, dried over MgSO₄, filtered and concentrated. This cruderesidue was subjected to column chromatography (600 g silica, 100mL/min, 0% to 60% EtOAc/hexanes) to give(R)-2-((S)-1,1-dimethylethylsulfinanmido)-N-(4-methoxybenzyl)-N-methyl-2-(2,4,6-trifluorophenyl)propane-1-sulfonamideas a 4:1 mixture with its diastereomer (14.5 g total mass, 37%).

This material was further subjected to SFC chromatography (TharSFC80,Chiralpak OJ-H, 21×250 mm, 5 μm, 200 bar with 5% MeOH, 55 g/min, 35° C.)to give(R)-2-((S)-1,1-dimethylethylsulfinamido)-N-(4-methoxybenzyl)-N-methyl-2-(2,4,6-trifluorophenyl)propane-1-sulfonamide).

The above material was treated according to Scheme 1a, Steps 4-6 toafford Example 18,dihydro-2,5(R)-dimethyl-5-(2,4,6-trifluorophenyl)-2H-1,2,4-thiadiazin-3(4H)-imine-1,1-dioxide.LCMS (conditions A): t_(R)=1.45 min, m/e=308.2 (M+H).

To a degassed solution the tert-butyl carbamate (Scheme 3) (348 mg,0.794 mmol) in MeOH (10 mL) was added 20% Pd(OH)₂/C (50% water) (52 mg,0.074 mmol). The flask was purged with H₂ and allowed to stir at RTunder a balloon of Hz for 2.75 hours. The mixture was purged with N₂,filtered through Celite and concentrated. The crude product was purifiedvia flash chromatography (SiO₂:gradient elution 100:0 to 95:5CH₂Cl₂:MeOH) to afford Ex. 19 (69 mg). LCMS (conditions A): t_(R)=2.00min, m/e=260.1 (M+H).

To the bromide (Table IIb, entry 13) (0.8 g, 1.8 mmol) in DMF (6 mL) wasadded N-chlorosuccinimide (0.7 g, 5.5 mmol). The reaction was warmed to60° C. and stirred for 5 h. Ethyl acetate was added and the mixture waswashed with saturated NaHCO₃ (aq), water, and brine. The organic layerwas dried (MgSO₄), filtered, and concentrated in vacuo. The residue waspurified by silica gel chromatography (0-30% EtOAc/hex over 30 minutes)to provide a white foam that was further purified by reverse phasechromatography (C18: gradient elution, 90:10:0.1 to 0:100:0.1water:MeCN:formic acid) to afford the chlorothiophene (0.63 g, 1.3mmol).

A solution of the nitro compound (Scheme 3b) (2.50 g, 6.0 mmol) in EtOH(150 mL) was degassed by bubbling N₂ through the solution for 3 min. Tothis solution was added Pd/C (10% w/w, 50% H₂O, 698 mg.). The mixturewas placed under an atmosphere of N₂. The atmosphere was evacuated andback-filled with H₂ (3×). The resulting mixture was stirred at RT undera Hz balloon for 2 h. The mixture was purged by bubbling N₂ through it,filtered through Celite and concentrated. The product was purified byfiltering through a small plug of silica gel column eluting with EtOActo afford the aniline (2.2 g, 97%).

TABLE IV The following anilines were prepared from the correspondingnitro compounds using a procedure similar to that described in Scheme10. Entries

1

2

3

4

5

Iodoaniline A Preparation:

NIS (2.52 g, 11.2 mmol) was added at 0° C. to a solution of the aniline(3.6 g, 9.31 mmol, Scheme 10) in DMF (40 mL). After 60 minutes at 0° C.and 60 min at RT, the reaction was quenched with saturated aq. NaHCO₃(aq), extracted with EtOAc (3×), and the combined organic layers driedover Na₂SO₄. After removal of the volatiles under reduced pressure, theresidue was subjected to silica gel chromatography (gradient elution100:0 to 70:30 hexanes:EtOAc) to give the iodoaniline (3.2 g, 67%).

Bromoaniline B Preparation:

NBS (1.05 g, 6.21 mmol) was added at RT to a solution of the aniline(2.0 g, 5.17 mmol, Scheme 10) in DMF (21 mL). After 30 minutes, thereaction was quenched with 10% aq. Na₂SO₃ (aq), diluted with EtOAc, andthe organic layer was washed with saturated aq. NaHCO₃ (2×), brine (1×)and dried over Na₂SO₄. After removal of the volatiles under reducedpressure, the residue (2.57 g) was subjected to silica gelchromatography (gradient elution 100:0 to 50:50 hexanes:EtOAc) to givethe bromoaniline (2.065 g, 86%).

A solution of the nitro compound (Entry 9, Table IIb) (515 mg, 1.19mmol) in 1:1 ELOH:THF (24 mL) in a pressure vessel was degassed bybubbling N₂ through it for 5 min. To this solution was added PtO₂ (27mg, 0.12 mmol). The vessel was sealed. The vessel was then evacuated andbackfilled with N₂ (3×). The vessel was then evacuated and purged withH₂ (3×). The vessel was pressurized to 60 psi with H₂ and shaken at RTovernight. After that time, the vessel was purged with N₂. The mixturewas then filtered through Celite. The solvent was removed in vacuo toafford the aniline (500 mg, 100%).

TABLE IVa The following compound was prepared from the correspondingnitro compound (Table IIId) according the methods described in Scheme11a:

Step 1:

To a flask containing the aniline (Scheme 11a) (100 mg, 0.25 mmol) and2-methyl-1,3-oxazole-4-carboxylic acid (47 mg, 0.37 mmol) was addedBOPCl (145 mg, 0.57 mmol). The flask was sealed and purged with N₂. Tothe flask was added pyridine (1.0 mL). The resultant solution wasstirred at RT for 1 hour. After that time, the solution was partitionedbetween EtOAc and water. The mixture was filtered through Celite toremove the solids. The aqueous layer was extracted with EtOAc (3×). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated. The crude product was purified via flashchromatography (SiO₂:gradient elution 100:0 to 65:35 hexanes:EtOAc) toafford the amide (81 mg, 64%).

Step 2:

To a solution of the amide from step 1 (81 mg, 0.16 mmol) in CH₂Cl₂(1.5mL) was added TFA (1.5 mL). The resultant solution was stirred at RT for2 hours. The solution was concentrated in vacuo to afford Ex. 20 (83 mg)as the trifluoroacetate salt. LCMS data: (method D): t_(R)=1.75 min,m/e=412.0 (M+H)

Step 1:

To a slurry of methyl 5-chloropyrazine-2-carboxylate (250 mg, 1.45 mmol)in EtOH (5 mL) was added potassium carbonate (300 mg, 2.18 mmol). Theresultant solution was stirred at RT for 2 hours. The mixture wasconcentrated. The residue was partitioned between water and CH₂Cl₂. Theaqueous layer was extracted with CH₂Cl₂ (3×). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated to afford ethyl5-ethoxypyrazine-2-carboxylate (110 mg, 39%) as a yellow solid.

Step 2

To a solution of the material from step 1 (110 mg, 0.60 mmol) in THE (3mL) was added a solution of LiOH (2M in water, 0.90 mL, 1.8 mmol). Thesolution was stirred at RT for 1 h. The solution was adjusted to pH 1using 1M HCl (aq.). The aqueous layer was extracted with EtOAc (3×). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated to afford the acid (75 mg, 74%).

TABLE IVb The following pyrazine carboxylic acids were prepared using aprocedure similar to that described in Scheme 11c using the appropriatealcohol in step 1. Modifications fo specific examples are listed belowthe table. Entries

1

2^(a)

3^(b)

4^(a)

5^(b)

6^(c)

7 ^(a)Step 1 modification: the ether was purified via flashchromatography (SiO₂ gradient elution 100:0 to 70:30 hexanes:EtOAc).^(b)Step 1 modification: the ether was purified via flash chromatography(C₁₈ gradient elution 90:10:0.1 to 0:100:0.1 water:MeCN:formic acid).^(c)Step 2 modification: the pyrazine acid was purified via flashchromatography (C₁₈ gradient elution 90:10:0.1 to 0:100:0.1water:MeCN:formic acid).

Step 1:

To a solution of methyl 5-chloropyrazine-2-carboxylate (500 mg, 2.90mmol) and 3-(trifluoromethyl)-1H-pyrazole (591 mg, 4.35 mmol) in DMF (7mL) was added potassium carbonate (591 mg, 4.35 mmol). The resultantsolution was stirred at RT overnight. The mixture was partitionedbetween water and EtOAc and separated. The organic layer was dried overNa₂SO₄, filtered and concentrated to afford the biaryl ester (560 mg,71%).

Step 2

The acid was formed using a procedure similar to that described inScheme 11c step 2.

TABLE IVc The following pyrazine carboxylic acids were prepared using aprocedure similart o that described in Scheme 11d using the appropriatepyrazole. Entries

1

2

Step 1

A degassed mixture of 5-chloropyrazine-2-carboxylate (500 mg, 2.90mmol), Cs₂CO₃ (1.1 g, 3.5 mmol), Pd(dppf)Cl₂CH₂Cl₂ (237 mg, 0.29 mmol)and thiophen-3-ylboronic acid (445 mg, 3.5 mmol) in dioxane (10 mL) washeated to reflux for 2 hours. The mixture was concentrated. The residuewas partitioned between water and CH₂Cl₂ and filtered through Celite.The aqueous layer of the filtrate was extracted with CH₂Cl₂ (3×). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated. The residue was purified via flash chromatography (SiO₂gradient elution 100:0 to 10:90 hexanes:EtOAc) to afford the biarylester (560 mg, 88%).

Step 2

The acid was formed using a procedure similar to that described inScheme 11c step 2.

A solution of the nitro compound (Table lie, entry 1, 1.70 grams, 3.7mmol) in THF:EtOH:H₂O (30 mL, 3:1:0.3) was degassed by bubbling N₂through the solution for 3 min. To the solution was added Zn (2.4 g, 37mmol) and NH₄Cl (996 mg, 18 mmol). The resultant mixture was heated toreflux under an atmosphere of N₂ for 3 hours. The mixture was filteredthrough celite and concentrated. The residue was purified via reversephase flash chromatography (C₁₈, gradient elution 90:10:0.1 to 0:100:0.1H₂O:MeCN:formic acid). The resultant formate salt was partitionedbetween EtOAc and sat NaHCO₃ (aq.). The aqueous layer was extracted withEtOAc (3×). The combined organic layers were dried over Na₂SO₄, filteredand concentrated to afford the aniline (847 mg, 54%).

TABLE IVd The following compounds were prepared according the methodsdescribed in Scheme 11f except they were purified via SiO₂ flashchromatography: Entries

1

2

3

4

5

Step 1

To 5-hydroxypyridine-2-carboxylic acid (4.40 g, 32 mmol) suspended inmethanol (77 mL) was added thionyl chloride (6.9 mL, 95 mmol) dropwise.The reaction was warmed to reflux and stirred for 22 h. After cooling toroom temperature, the mixture was concentrated in vacuo to provide themethyl ester (5.71 g, 95%).

Step 2

To the methyl ester (0.40 g, 2.1 mmol) formed in step 1 in DMF (3 mL)was added potassium carbonate (0.88 g, 6.3 mmol) and cyclopropylmethylbromide (0.41 mL, 4.2 mmol). The reaction was warmed to 65° C. andstirred for 18 h. The reaction was cooled to room temperature and thenconcentrated in vacuo. The residue was triturated with EtOAc andfiltered washing with EtOAc. The filtrate was concentrated in vacuo toprovide a crude product that was purified by silica gel chromatography(0-50% EtOAc/hex over 30 minutes) to provide the cyclopropylmethyl ether(0.27 g, 61%).

Step 3

To the product of step 2 (0.27 g, 1.3 mmol) in THF (2 mL) was added 2NLiOH_((aq.)) (1.9 mL, 3.9 mmol). The reaction was stirred at roomtemperature for 2 h. The pH was adjusted to pH 4 using saturated aqueouscitric acid. The mixture was extracted with EtOAc. The combined organiclayers were washed with brine, dried (MgSO₄), filtered, and concentratedin vacuo to provide the carboxylic acid (0.23 g, 94%).

Step 1

To 3,5-difluoropyridine-2-carboxylic acid (3.0 g, 19 mmol) in THF (30mL) in a glass tube reaction vessel was added 2N LiOH_((aq)). Thereaction mixture was capped and warmed to 100° C. The reaction wasstirred for 18 h and then cooled to room temperature. TFA (5 mL) wasadded and the reaction was concentrated in vacuo. The residue waspurified by reverse phase chromatography [C18 (360 g) 0.1% formicacid/water for 20 minutes followed by 0-100% 0.1% formicacid/acetonitrile//0.1% formic acid/water] to provide the hydroxypyridine (2.1 g) as a ˜1:1 mixture of starting material and product. Themixture was carried on directly.

Step 2

To the hydroxy pyridine prepared in the previous step (2.1 g) inmethanol (20 mL) was added thionyl chloride (2.2 mL, 31 mmol). Thereaction was warmed to 70° C. and stirred for 18 h. The reaction wascooled to room temperature and concentrated in vacuo. The residue waspurified by reverse phase chromatography [C18 (205 g), 0-100% over 20minutes 0.1% formic acid/acetonitrile//0.1% formic acid/water] toprovide the methyl ester (1.0 g, 31% over 2 steps).

Step 1

To the methyl 5-hydroxypicolinate hydrochloride prepared in step 1 ofScheme 11 g (0.21 g, 1.1 mmol) in a glass tube reactor in acetonitrile(4 mL) was added water (4 mL), potassium carbonate (5.5 g, 40 mmol) and2-chloro-2,2-difluoroacetophenone (1.0 g, 5.5 mmol). The reaction vesselwas capped and warmed to 80° C. The reaction was stirred at 80° C. for 3h and cooled to room temperature. The mixture was filtered washing withether. The filtrate was washed with ether. The ether washes werecombined and washed with water and brine, dried (MgSO₄), filtered, andconcentrated in vacuo to provide a tan oil. The oil was purified bysilica gel chromatography (0-40% EtOAc/hex over 30 minutes) to providethe ether (0.13 g, 60%).

Step 2

Using the procedure described in step 3 of Scheme 11 g, the product ofstep 1 was converted to the carboxylic acid.

Step 1

To 5-hydroxypyrazine-2-carboxylic acid methyl ester (2.0 g, 13 mmol) ina glass tube reaction vessel in DMF (26 mL) was added potassiumcarbonate (5.3 g, 39 mmol) and sodium 2-chloro-2,2-difluroacetate (4.0g, 26 mmol). The reaction vessel was capped and warmed to 100° C. Thereaction was stirred for 30 minutes and cooled to room temperature. Thereaction was filtered washing with EtOAc. The filtrate was concentratedin vacuo. The residue was taken up into EtOAc and washed with brine. Theorganic layer was dried (MgSO₄), filtered, and concentrated in vacuo.The residue was purified by silica gel chromatography (0-40% EtOAc/hex)to give methy-5-(difluoromethoxy)pyrazine-2-carboxylate (0.09 g, 0.46mmol) (0.40 g, 20%).

Step 2

To the product of step 1 (0.09 g, 0.46 mmol) was added 3N HCl_((aq)).The reaction was heated in a sealed microwave reactor vial to 100° C.for 2 h. The reaction was concentrated in vacuo to provide thecarboxylic acid (0.88 g, 100%).

TABLE IVf The following pyridine carboxylic acids were prepared fromeither intermediate B, Scheme 11g or the hydroxypyridine from Scheme 11husing conditions similar to those described in Scheme 11g steps 2 and 3.Modifications of the experimental conditions are noted below the table.Entries

1^(a)

2 ^(b)

3 ^(b)

4 ^(b)

5 ^(c, g)

6 ^(c, g)

7 ^(f)

8 ^(d)

9 ^(c) Alkylation conditions: ^(a)Cs₂CO₃, NaI, 150° C., 7 h; ^(b) rt;^(c) 45° C.; ^(d) 100° C.; ^(e) 130° C., microwave, 1 h; ^(f) 70° C.Hydrolysis conditions: ^(g) See Scheme 11j, step 2.

Step 1

To the hydroxypyridine prepared in Scheme 11 h (0.19 g, 1.1 mmol) inacetonitrile (4 mL) and water (4 mL) was added potassium carbonate (5.5g, 40 mmol) and 2-chloro-2,2-difluoroacetophenone. The glass reactiontube was sealed and warmed to 80° C. After 3.5 h, the reaction wascooled to room temperature and filtered washing with EtOAc. The filtratewas extracted with ether. The combined ether layers were washed withwater and brine, dried (MgSO₄), filtered, and concentrated in vacuo. Theresidue was purified by silica gel chromatography (0-30% EtOAc/hex over30 minutes) to provide product (0.15 g, 60%).

Step 2

The product of step 1 was converted to the carboxylic acid using theconditions found in step 3 of Scheme 11 g.

3-Cyanoisoquinoline (1.047 g, 6.79 mmol) was suspended in 6 M HCl (aq)(50 mL) and refluxed at 95° C. for 18 h. The reaction was cooled to RT,and the volatiles removed under vacuum to provide the carboxylic acid(2.07 g) that was used as is.

4-Pentafluorosulfur benzoic acid was obtained in two steps from4-bromophenyl sulfurpentafluoride according to the literature procedureby Zarantonello et al., J. Fluor. Chem. 2007, 128, 1449-1453.

Step 1

To 2-chloro-5-fluoropyrimidine (2 g, 15 mmol) in a 250-mL round bottomflask was added DMA (8 mL), tris(dibenzylideneacetone)dipalladium (0.544g, 0.6 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.67 g, 1.2 mmol),zinc cyanide (1.15 g, 9.8 mmol), and zinc dust (0.237 g, 3.62 mmol). Theflask was capped, flushed with nitrogen, and stirred for 2.5 h at 100°C. The reaction was cooled to room temperature, filtered through celite,and washed with DCM. The filtrate was poured into water and extractedwith DCM. The combined organic layers were dried (MgSO₄), filtered, andconcentrated in vacuo. The residue was purified by silica gelchromatography (0-10% EtOAc/hexanes over 20 minutes) to provide thenitrile compound (0.58 g, 31%).

Step 2

To the nitrile compound prepared in Step 1 (0.51 g, 4.14 mmol) stirringin 5 mL MeOH was added 5 mL conc. HCl. The reaction was fitted with areflux condenser and heated at 80° C. for 2 hours, then cooled to roomtemperature. Saturated aqueous sodium bicarbonate was added and stirredfor 1 hour at room temperature. The mixture was acidified to pH 4 using1 N HCl (aq) and extracted with EtOAc. The combined organic layers weredried (MgSO₄), filtered, and concentrated in vacuo to provide the methylester (0.256 g, 40%).

Step 3

To the methyl ester compound prepared in Step 2 (0.256 g, 1.64 mmol) in6 mL 1:1:1 THF:H₂O:MeOH was added LiOH hydrate (0.272 g, 4.04 mmol), andthe mixture stirred at room temperature for 1 hour. The reaction wasacidified to pH 4 using 1 N HCl (aq) and extracted with EtOAc. Thecombined organic layers were dried (MgSO₄), filtered, and concentratedin vacuo to provide the carboxylic acid (0.136 g, 58%).

TABLE IVg The following acids were made using methods similar to thosedescribed in Scheme 11n using the appropriate aryl chloride (entries1-3) or bromide (entries 4 and 5): Entries

1

2

3

4

5

TABLE IVh The following acid was made using methods similar to thosedescribed in Scheme 11n, Step 3: Entry Starting material Acid 1

TABLE IVi The following acid was made according to methods similar tothose described in Scheme 11n, using Step 1 and then Step 3, omittingStep 2: Entry Starting material Acid 1

To 2-bromo-5-(methyl-D₃)-pyrazine (400 mg, 2.27 mmol) stirring in 8 mLanhydrous THF at −78° C. under N₂ atmosphere was slowly added n-BuLi(2.5 M in hexanes, 1.14 mL, 2.85 mmol). The reaction was stirred for 30minutes at this temperature, upon which carbon dioxide was bubbledthrough the solution for 15 minutes via cannulating needle. The coldbath was removed and the reaction allowed to come to room temperatureslowly over 1 hour. Water was then added and the reaction was extractedwith ethyl acetate. The organics were combined, dried (MgSO₄), andconcentrated in vacuo to provide an oil (120 mg, 38%) that was usedwithout further purification.

3-Fluoro-5-(trifluoromethyl)picolinic acid was prepared from2-bromo-3-fluoro-5-(trifluoromethyl)pyridine using a procedure similarto that described above in Scheme 11o.

To 5-chloropicolinic acid (0.3 g, 1.9 mmol) stirring at room temperaturein 6 mL THE and 1 drop of DMF was slowly added dropwise oxalyl chloride(0.48 mL, 5.7 mmol). Vigourous outgassing was observed. The reaction wasstirred at room temperature for 1.5 hours, then concentrated to drynessin vacuo and the product used without further purification.

TABLE IVj The following acid chlorides were made using methods similarto those described in Scheme 11p from the appropriate carboxylic acid.Entries

1

2

Step 1:

To 3,5-difluoropyridine-2-carboxylic acid (2 g, 12.6 mmol) stirring in20 mL 4:1 toluene:MeOH at room temperature was slowly added dropwisetrimethylsilyldiazomethane (2.0 M in hexanes, 15.1 mmol, 7.5 mL). Thereaction was allowed to stir for 30 minutes, and then was concentratedto dryness in vacuo and used without further purification.

Step 2

To the methyl ester prepared in step 1 (1.09 g, 6.3 mmol) stirring atroom temperature in 20 mL MeOH in a 350-mL sealed vessel was added 25weight % sodium methoxide in methanol (3.4 g sodium methoxide, 13.6 gsolution, 63 mmol). The reaction was flushed with nitrogen, sealed, andstirred 16 hours in a 100° C. oil bath. The next day the reaction wascooled to room temperature and acidified to pH 4 using 1 N HCl. Thesolution was extracted with 1:1 EtOAc:THF (250 mL). The organic layerwas dried (MgSO₄), filtered, and concentrated in vacuo. The residue waspurified by silica gel chromatography (0-60% EtOAc/hexanes over 20minutes) to provide the desired bis-methoxy compound (0.53 g, 43%).

Step 3

The methyl ester was converted to the carboxylic acid using methodssimilar to those described in Scheme 11n, Step 3.

TABLE IVk The following acids were made using methods similar to thosedescribed Scheme 11q using the appropriate aryl chloride: Entries

1

2

Step 1

To 2-fluoro-5-formylpyridine (1.57 g, 12.55 mmol) stirring in anhydrousTHF (20 mL) at 0° C. under a nitrogen atmosphere was slowly added(trifluoromethyl)-trimethylsilane (2.67 g, 18.78 mmol). The mixture wasstirred at 0° C. for 15 minutes, and then tetrabutylammonium fluoride(1.0 M in THF, 31.38 mL, 31.38 mmol) was slowly added dropwise, uponwhich the ice bath was removed, and the reaction was allowed to stir atroom temperature overnight (total reaction time 16 hours). The reactionwas then poured into water and extracted with EtOAc. The combinedorganic layers were dried (MgSO₄), filtered, and concentrated in vacuo.The residue was purified by silica gel chromatography (0-20%EtOAc/hexanes over 20 minutes) to provide the trifluoromethyl alcoholproduct (2.01 g, 82%).

Step 2

To the trifluoromethyl alcohol prepared in step 1 (1 g, 5.12 mmol)stirring in anhydrous DCM (20 mL) was added Dess-Martin periodinane(2.63 g, 6.14 mmol). The reaction was stirred at room temperatureovernight (total reaction time 16 hours). Hexanes were added upon whicha precipitate formed. The solid was filtered off and washed with DCM.The filtrate was taken and poured into saturated aqueous sodiumbicarbonate and extracted with DCM. The combined organic layers weredried (MgSO₄), filtered, and concentrated in vacuo. The residue waspurified by silica gel chromatography (0-20% EtOAc/hexanes over 20minutes) to provide the trifluoromethyl ketone product (0.453 g, 46%).

Step 1

The carboxylic acid (1.5 g, 7.84 mmol) was converted to the methyl esterusing methods similar to those described in Scheme 11q, Step 1. Thecrude reaction was evaporated to dryness in vacuo, and purified bysilica gel chromatography (0-30% EtOAc/hexanes over 20 minutes, 30-40%EtOAc/hexane from 20-30 minutes) to provide the methyl ester product asa solid (1.02 g, 63%).

Step 2

To a mixture of methyl 5-(trifluoromethyl)pyridine-2-carboxylateprepared above (0.2 g, 0.97 mmol) and (trifluoromethyl)trimethylsilane(0.173 g, 1.22 mmol) stirring at −78° C. in pentante (3 mL) under anitrogen atmosphere was slowly added tetrabutylammonium fluoride (1.0 Min THF, 25 μL, 0.024 mmol). The reaction was allowed to come to roomtemperature and stirred overnight (total reaction time 16 hours). Atthat time, 2 N HCl was added, and the mixture was stirred vigorously atroom temperature for 2 hours. The solution was extracted with DCM. Thecombined organic layers were dried (MgSO₄), filtered, and concentratedin vacuo. The residue was purified by silica gel chromatography (0-20%EtOAc/hexanes over 20 minutes) to provide the trifluoromethyl ketoneproduct (0.084 g, 35%).

TABLE IVl The following pyrazine carboxylic acid was prepared using aprocedure similar to that described in Scheme 11e. Entry 1

A large microwave tube was charged sequentially with MeCN (9 mL),tert-butyl nitrite (0.15 mL, 1.2 mmol), and copper(II) bromide (0.331 g,1.48 mmol). The tube was crimp sealed and immersed in an oil bath at 60°C. To the resulting black-green mixture was added a solution of1,1-dimethylethyl[5(R)-(5-amino-2,4-difluorophenyl)dihydro-2,5-dimethyl-1,1-dioxido-2H-1,2,4-thiadiazin-3(4H)-ylidene]carbamate(Table IV, Entry 2, 500 mg, 1.24 mmol) in MeCN (3 mL) via syringe over˜2 min. After the addition was complete, the reaction was stirred at 60°C. for 20 min. At that time, the reaction was cooled, diluted withEtOAc, and filtered through Celite. The filtrate was diluted with waterand EtOAc. The phases were separated and the aqueous layer was extracted2× with EtOAc. The organic portions were combined, washed with sat, aq.NaHCO₃ and brine, dried over MgSO₄, filtered, and concentrated. Thiscrude sample was subjected to column chromatography (80 g silica, 60mL/min, 0% to 50% EtOAc/hexanes) to give product 1,1-dimethylethyl[5(R)-(5-bromo-2,4-difluorophenyl)dihydro-2,5-dimethyl-1,1-dioxido-2H-1,2,4-thiadiazin-3(4H)-ylidene]carbamate (0.30 g, 52%).

Step 1

To a suspension of 5-bromopicolinic acid (20.2 g, 100 mmol) in 200 mL oftoluene was added thionyl chloride (11 mL, 150 mmol). The mixture wasstirred at room temperature for 20 min and then heated to reflux for 30min. The resulting solution was cooled to room temperature andconcentrated to dryness. The crude product 5-bromopicolinoyl chloridewas used directly in the next step.

Step 2

After addition of THF (200 mL) and Et₃N (42 mL) to the above residue,the mixture was cooled in an ice-water bath. Benzyl alcohol (31.1 mL,300 mmol) was added slowly. The mixture was warmed up to roomtemperature and stirred overnight.

The reaction mixture was diluted with ether, washed with sat.NaHCO_(3(aq.)), H₂O, brine and then dried (MgSO₄). After concentrationand crystallization, the desired product benzyl 5-bromopicolinate (20.6g) was obtained.

Step 3

To a solution of benzyl 5-bromopicolinate (876 mg, 3.0 mmol) in THF (10mL) was added Pd(PPh₃)₄(173 mg, 0.15 mmol) under N₂. After addition of asolution of cyclopropylzinc bromide in THF (0.5 M, 10 mL), the mixturewas heated at 80° C. for 3 hours and then cooled to room temperature.The reaction mixture was quenched with sat. NH₄Cl (aq) and extractedwith EtOAc (3×), The organic layer was washed with sat. NaHCO_(3(aq.)),brine, and dried (MgSO₄). The product benzyl 5-cyclopropylpicolinate(510 mg) was obtained by silica gel chromatography (elution with 0-15%EtOAc/Hex, then 15% EtOAc/Hex).

Step 4

To a solution of benzyl 5-cyclopropylpicolinate in MeOH (15 mL) wasadded 20% Pd(OH)₂/C (100 mg). The hydrogenolysis with H₂ was carried outat room temperature under a H₂ balloon. The desired product5-cyclopropylpicolinic acid (305 mg) was obtained after filtration andconcentration.

Step 1

A mixture of benzyl 5-bromopicolinate (2.92 g, 10 mmol), potassiumisopropenyl trifluoroborane (3.05 g, 21 mmol), Pd(dppf)Cl₂ (445 mg, 0.54mmol), and Et₃N (1.4 mL) in isopropyl alcohol (20 mL) was degassed withN₂ and heated at 80° C. for 7 h. The mixture was cooled to roomtemperature and diluted with EtOAc. The organic layer was washed withH₂O, 5% citric acid, sat.NaHCO_(3 (aq.)) and brine, then dried (MgSO₄)and concentrated. The product benzyl 5-isopropenylpicolinate (1.27 g)was obtained by silica gel chromatography (elution with 0-16%EtOAc/Hex).

Step 2

A solution of benzyl 5-isopropenylpicolinate (1.27 g, 5 mmol) in MeOH(25 mL) was subjected to hydrogenation with 20% Pd(OH)₂/C (200 mg) witha H₂ balloon for 2 h. The product 5-isopropenylpicolinic acid (780 mg)was obtained by filtration and concentration.

Step 1

A mixture of 5-bromo-3-fluoropicolinonitrile (1.0 g, 5 mmol),Pd(dppf)Cl₂ (82 mg, 0.1 mmol) and cesium carbonate (3.26, 10 mmol) inTHF (20 mL) was degassed with N₂. After addition of a solution oftriethylborane (1.0 M THF, 10 mL), the mixture was heated at 65° C. for5 h. The mixture was cooled down to room temperature, and then furthercooled down in an ice bath. Into the mixture was added a solution ofNaOH (1.2 g) in 20 mL of 1H₂O, followed by H₂O₂ (30% aqueous 7 mL). Themixture was stirred at 0° C. for 30 min and extracted with ether (4×).The organic layer was washed with brine and dried (MgSO₄), andconcentrated. The product 5-ethyl-3-fluoropicolinamide (370 mg) wasobtained from silica gel chromatography (elution with 0-40% EtOAc/Hex).

Step 2

A mixture of amide (475 mg, 2.8 mmol) in 10 mL of cone. HCl was heatedat reflux for 5 h. The mixture was concentrated and dried in vacuo togive the product 5-ethyl-3-fluoropicolinic acid.

Step 1

To solution of 5-bromo-3-fluoropicolinonitrile (603 mg, 3.0 mmol) andPd(PPh₃)₄ (173 mg, 0.15 mmol) in 10 mL of THF was added cyclopropyl zincbromide (0.5 M, 10 mL) under N₂. After being heated 80° C. for 4 h, themixture was cooled to room temperature and quenched with sat. NH₄Cl(aq). The mixture was extracted with EtOAc (3×) and the combined organiclayers were washed with sat. NaHCO_(3 (aq.)) and brine, dried (MgSO₄),and concentrated. The crude product was purified by silica gelchromatography (elution with 0-8% EtOAc/Hex) to afford5-cyclopropyl-3-fluoropicolinonitrile (406 mg).

Step 2

The product of step 1 was heated at reflux in 10 mL of cone. HClovernight. After concentration, the solid product5-cyclopropyl-3-fluoropicolinic acid (400 mg) was washed with cold waterand dried in vacuo.

Step 1

A mixture of 1-(6-bromopyridin-3-yl)ethanone (200 mg, 1.0 mmol) and CuCN(179 mg, 2.0 mmol) in anhydrous DMF (5 mL) was heated at 110° C. for 18h under N₂. The mixture was cooled to room temperature and diluted withwater. After addition of EtOAc and filtration, the aqueous layer wasextracted with EtOAc. The organic layer was washed with sat. NaHCO₃(aq), brine, and then dried (MgSO₄) and concentrated. The product5-acetylpicolinonitrile (120 mg) was obtained by silica gelchromatography (elution with 0-20% EtOAc/Hex).

Step 2:

5-Acetylpicolinonitrile (146 mg, 1.0 mmol) in 5 mL of cone. HCl washeated at reflux for 2.5 h. The mixture was concentrated and dried invacuo. The crude product 5-acetylpicolinic acid was used without furtherpurification.

Step 1

A mixture of 5-acetylpicolinonitrile (146 mg, 1.0 mmol) and Deoxo-Fluor™(1.0 mL, 50% in toluene) was heated at 80° C. for 3 h under N₂. Themixture was cooled to room temperature and diluted with DCM. The organiclayer was washed with sat. NaHCO_(3 (aq.)), and brine, dried (MgSO₄) andconcentrated. The residue was purified by silica gel chromatography(elution with 0-15% EtOAc/Hex) to afford5-(1,1-difluoroethyl)picolinonitrile (120 mg).

Step 2:

5-(1,1-Difluoroethyl)picolinonitrile (120 mg, 0.71 mmol) in 9 mL ofcone. HCl was heated at 110° C. for 5 h. The mixture was concentrated.To the residue was added diisopropylethylamine (2 mL) and the mixturewas concentrated. The residue was dried in vacuo and used withoutfurther purification.

Step 1

A mixture of 6-bromonicotinaldehyde (11.2 g, 60 mmol) and CuCN (8.06 g,90 mmol) in DMF (100 mL) was heated at 120° C. for 3 h under N₂. Themixture was cooled to rt and diluted with EtOAc and filtered through apad of celite. The organic layer was washed with water and brine andthen dried (MgSO₄) and concentrated. The product 5-formylpicolinonitrile(4.55 g) was obtained by silica gel chromatography (elution with 0-20%EtOAc/Hex).

Step 2

A mixture of 5-formylpicolinonitrile (132 mg, 1.0 mmol) and Deoxo-Fluor®(1.0 mL, 50% in toluene) was stirred at room temperature 16 h. Afterdilution with DCM, the solution was washed with sat. NaHCO₃, brine, thendried (MgSO₄) and concentrated. The product5-(difluoromethyl)picolinonitrile (118 mg) was obtained by silica gelchromatography (elution with 0-10% EtOAc/Hex).

Step 3:

5-(Difluoromethyl)picolinonitrile (118 mg, 0.75 mmol) in 9 mL of cone.HCl was heated at 110° C. for 2.5 h. The mixture was cooled,concentrated and treated with diisopropylethylamine (2 mL). The mixturewas re-concentrated and dried in vacuo to give5-(difluoromethyl)picolinic acid that was used without purification.

Step 1

To a −78° C. solution of 5-formylpicolinonitrile (1.0 g, 7.58 mmol) andtetrabutylammonium triphenyldifluorosilicate (4.9 g, 9.10 mmol) in 60 mLof THF was added a solution of trimethyl(trifluoromethyl)silane (1.62 g,114 mmol). The mixture was stirred for 20 min at −78° C. Then thecooling bath was changed to an ice bath. After stirring for another 30min, the reaction was quenched with sat. NH₄Cl_((aq.)). The mixture wasextracted with EtOAc (3×). The organic layer was washed with sat.NaHCO_(3 (aq.)), brine, then dried (MgSO₄) and concentrated. The product5-(2,2,2-trifluoro-1-hydroxyethyl)picolinonitrile (600 mg) was obtainedby silica gel chromatography (elution with 0-40% EtOAc/Hex).

Step 2

A mixture of 5-(2,2,2-trifluoro-1-hydroxyethyl)picolinonitrile (202 mg,1.0 mmol), cone. HCl (0.5 mL) and cone. H₂SO₄ (0.25 mL) in 10 mL ofanhydrous MeOH was heated at reflux for 19 h. The solution wasconcentrated and neutralized with sat. NaHCO_(3 (aq.)). Extraction withEtOAc followed by concentration of the organic layer and purification ofthe residue by silica gel chromatography (elution with 0-45% EtOAc/Hex)afforded methyl 5-(2,2,2-trifluoro-1-hydroxyethyl)picolinate (76 mg).

Step 3

To a solution of methyl 5-(2,2,2-trifluoro-1-hydroxyethyl)picolinate (76mg, 0.32 mmol) in 3 mL of DCM was added triethylamine (0.22 mL),followed by a solution of methanesulfonyl chloride (45 mg, 0.39 mmol) in1 mL of DCM. The mixture was stirred at room temperature for 7 h andthen diluted with DCM. The solution was washed with 5% citric acid andsat. NaHCO₃ (aq.), dried (MgSO₄), and concentrated. The product methyl5-(2,2,2-trifluoro-1-(methylsulfonyloxy)ethyl)picolinate (95 mg) waspurified by chromatography.

Step 4

To a solution of methyl5-(2,2,2-trifluoro-1-(methylsulfonyloxy)ethyl)picolinate (95 mg, 0.3mmol) in 5 mL of MeOH was added 10% Pd/C (45 mg). Hydrogenation with 1atm H₂ was carried out at room temperature for 2 h. After the catalystwas removed by filtration, the filtrated was concentrated. The residuewas dissolved in DCM and washed with sat. NaHCO_(3 (aq.)), and brine.The solution was dried (MgSO₄) and concentrated to give methyl5-(2,2,2-trifluoroethyl)picolinate that was used without purification.

Step 5

A mixture of methyl 5-(2,2,2-trifluoroethyl)picolinate (57 mg, 0.26mmol) and LiOH (12.5 mg, 0.52 mmol) in 6 mL MeOH/water (5:1) was stirredat room temperature for 3.5 h.

The reaction mixture was acidified with 5% citric acid, and thenconcentrated. The residue was extracted with DCM (4×). The organic layerwas washed with brine and dried (Na₂SO₄). After concentration, theproduct 5-(2,2,2-trifluoroethyl)picolinic acid was dried in vacuo andused without further purification.

Step 1

To a 0° C. solution of 5-formylpicolinonitrile (490 mg, 3.71 mmol) in 15mL of MeOH was added NaBH₄ (140 mg, 3.71 mmol). The reaction mixture wasstirred at 0° C. for 1 h and quenched with 5% citric acid. After mostMeOH was removed by concentration, the residue was partitioned betweenDCM and sat. NaHCO_(3 (aq.)). The aqueous layer was extracted with DCM(10×). The organic layer was washed with brine and dried (Na₂SO₄) Theproduct 5-(hydroxymethyl)picolinonitrile (431 mg) was obtained byconcentration under vacuum.

Step 2

To a solution of 5-(hydroxymethyl)picolinonitrile (1.59 g, 11.9 mmol) in80 mL of DCM was added diisopropylethylamine (3.2 mL), followed by asolution of methanesulfonyl chloride (1.49 g, 13.0 mmol) in 20 mL of DCMat 0° C. The solution was stirred at 0° C. for 40 min and washed with 5%citric acid, sat. NaHCO_(3 (aq.)) and brine. After concentration, theresidue was purified by silica gel chromatography (elution with 0-30%EtOAc/Hex) to afford (6-cyanopyridin-3-yl)methyl methanesulfonate (2.33g).

Step 3

(6-Cyanopyridin-3-yl)methyl methanesulfonate (199 mg, 0.94 mmol) in 2 mLanhydrous EtOH was heated at 85° C. in a sealed tube for 3.5 h. Themixture was concentrated and purified by silica gel chromatography(elution with 0-25% EtOAc/Hex) to afford 5-(ethoxymethyl)picolinonitrile(104 mg).

Step 4

A solution of 5-(ethoxymethyl)picolinonitrile (104 mg) in 10 mL of conc.HCl was heated at reflux for 3.5 h. After concentration,diisopropylethylamine (3 mL) was added into the residue. The mixture wasconcentrated and dried in vacuo. The product 5-(ethoxymethyl)picolinicacid was used without further purification.

TABLE IVm The following acids were prepared using similar proceduresdescribed in Scheme 11ac, substituting the appropriate alcohol in Step3. Entries

1

2

3

TABLE V The following examples were prepared using a procedure similarto that described in Scheme 11b using the appropriate aryl amines andcarboxylic acids Examples (LCMS data listed with each compound: observedMH⁺, HPLC retention time and LCMS method)

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

40a

40b

40c

40d

40e

40f

40g

40h

40i

40j

40k

40l

40m

40n

40o

40p

40q

40r

40s

40t

40u

40v

40w

40x

40y

40z

40aa

40ab

40ac

40ad

40ae

40af

40ag

40ah

40ai

40aj

40ak

40al

40am

40an

40ao

40ap

40aq

40ar

40as

40at

40au

40av

40aw

40ax

40ay

40az

40ba

40bb

40bc

40bd

40be

40bf

40bg

40bh

40bi

40bj

40bk

40bl

40bm

40bn

40bo

40bp

40bq

40br

40bs

40bt

40bu

40bv

40bw

40bx

40by

40bz

40ca

40cb

40cc

40cd

40ce

40cf

40cg

40ch

40ci

40cj

40ck

40cl

40cm

40cn

40co

40cp

40cq

40cr

40cs

40ct

40cu

40cv

40cw

40cx

40cy

40cz

40da

40db

40dc

40dd

40de

40df

40dg

40dh

40di

40dj

40dk

40dl

40dm

40dn

40do

40dp

40dq

40dr

40ds

40dt

40du

40dv

40dw

40dx

40dy

40dz

40ea

40eb

40ec

40ed

40ee

40ef

40eg

40eh

40ei

40ej

40ek

40el

40em

40en

40eo

40ep

40eq

40er

40es

40et

40eu

40ev

40ew

40ex

40ez

40fa

40fb

40fc

40fd

40fe

40ff

40fg

40fh

40fi

40fj

40fk

40fl

40fm

40fn

40fo

40fp

40fq

40fr

40fs

40ft

40fu

40fv

40fw

40fx

40fy

40fz

40ga

40gb

40gc

40gd

40ge

40gf

40gg

40gh

40gi

40gj

40gk

40gl

40gm

40gn

40go

40gp

40gq

40gr

40gs

40gt

40gu

40gv

40gw

40gx

40gy

40gz

40ha

40hb

40hc

40hd

40he

40hf

40hg

40hh

40hi

40hj

40hk

40hl

40hm

40hn

40ho

40hp

40hq

40hr

40hs

40ht

40hu

40hv

40hw

40hx

40hy

40hz

40ia

40ib^(a)

40ic^(a)

40id^(a)

40ie

40if

40ig

40ih^(a)

40ii

40ij ^(a)The hydroxypyrazine amides were formed using thecyclopropylmethylether pyrazine acid (Entry 5, Table IVb) instead of1,3-oxazole-4-carboxylic acid in step 1 of Scheme 11b.

Step 1:

To a solution of the aniline from Table IV entry 1 (80 mg) and Et₃N (50μL) in CH₂Cl₂ (2 mL) was added acetyl chloride (1.2 eq.). The resultingsolution was stirred at RT for 2 hours. Water was added and the aqueouslayer was extracted with CH₂Cl₂, dried over Na₂SO₄, filtered andconcentrated. The crude residue was purified via flash chromatography(SiO₂:0 to 60% EtoAc in hex).

Step 2

Example 41 was prepared as the TFA salt from the product of step 1 usinga method similar to that described in Scheme 11b step 2. LCMS data:(method D): t_(R)=0.91 min, m/e=311 (M+H).

To a mixture of the aniline from Scheme 10 (50 mg, 0.13 mmol) andpotassium carbonate (18 mg, 0.13 mmol) in 1:1 acetone:water (4 mL) wasadded benzyl chloroformate (0.028 mL, 0.19 mmol). The mixture wasstirred at RT for 30 min. Water was added and the mixture was extractedwith CH₂C12 (3×). The combined organic layers were dried over Na₂SO₄,filtered and concentrated. The crude product was purified via flashchromatography (SiO₂:gradient elution 100:0 to 70:30 hexanes:EtOAc) toafford the carbamate.

Example 41b was prepared as its TFA salt from the above carbamate usinga method similar to that described in Scheme 11b step 2. LCMS data:(method D): t_(R) 1.88 min, m/e=421.0 (M+H).

Step 1

To a mixture of the aniline (200 mg, 0.517 mmol, Scheme 10) and DIEA(0.36 mL, 2.07 mmol) in CH₂Cl₂ (2 mL) at RT was added dropwiseethylsulfonyl chloride (0.074 mL, 0.775 mmol). After 18 h, the reactionwas quenched with 1 M HCl and the aqueous layer was extracted with DCM.The combined organic layers were dried over MgSO₄ and concentrated underreduced pressure.

Step 2

Example 41c was prepared from the above material using a method similarto that described in Scheme 11b step 2. After deprotection, theresulting residue was purified by reverse phase chromatography (C18:gradient elution, 90:10:0.1 to 0:100:0.1 water:MeCN:TFA) to provideExample 41c as its TFA salt. LCMS (conditions D): t_(R)=1.64 min,m/e=379.0 (M+H).

TABLE Va The following examples were prepared using a method similar tothat described in Scheme 12c. Examples (LCMS data listed with eachcompound: observed MH⁺, HPLC retention time and LCMS method) 41d

41e

To the aniline (Scheme 10, 70 mg, 0.18 mmol) in 2 mL DCM was addedacetic anhydride (19 μL, 0.2 mmol) and triethylamine (29 μL, 0.2 mmol).The reaction was stirred for 3 hours at room temperature, then pouredinto water. The mixture was extracted with DCM. The combined organiclayers were dried (MgSO₄), filtered, and concentrated in vacuo. Theresidue was purified by silica gel chromatography (0-50% EtOAc/hexanesover 30 minutes) to provide a methyl amide product. This material wasstirred in 2 mL 20% TFA/DCM for 1 hr and then concentrated in vacuo toprovide Example 41f as a trifluoroacetate salt (0.041 g, 69%). LCMSdata: (method A): t_(R)=2.96 min, m/e=379.2 (M+H).

TABLE VI The following examples were prepared using a method similar tothat described in Scheme 12 using the appropriate acid chlorides andaryl amines. Examples (LCMS data listed with each compound: observedMH⁺, HPLC retention time and LCMS method) 42

42a

A mixture of 2-chloro-3-fluoro aniline (252 mg, 0.60 mmol), ammoniumformate (5.0 g, 79 mmol) in 25 mL of isopropanol was heated at 70° C.overnight. After filtration and concentration, the residue was purifiedby silica gel chromatography (elution with 0-30% EtOAc/Hex) to affordthe 3-fluoro aniline product (150 mg).

A mixture of aniline (96 mg, 0.25 mmol, Scheme 10), the acid (Scheme 1Ix, 81 mg, 0.45 mmol), HATU (230 mg, 0.60 mmol), and DIEA (0.36 mL, 2.0mmol) in 5 mL of DCM was stirred at room temperature overnight. Thereaction mixture was diluted with DCM, washed with 5% citric acid, sat.NaHCO₃, and brine. After drying (MgSO₄) and concentration, the residuewas subjected to silica gel chromatography (elution with 0-25%EtOAc/Hex). The resulting product was dissolved in 6 mL of 25% ofTFA/DCM and stirred at room temperature for 1 h. Concentration anddrying in vacuo provided Example 42b (143 mg) as a TFA salt. LCMS(conditions D): t_(R)=1.91 min, m/e=450.2 (M+H).

TABLE VIb The following examples were prepared from the correspondinganiline and carboxylic acid using a procedure similar to that describedin Scheme 12f. Examples (LCMS data listed with each compound; observedMH⁺, HPLC retention time and LCMS method) 42c

42d

42e

42f

42g

42h

42i

42j

42k

42l

42m

42n

42o

42p

42q

42r

42s

42t

42u

42v

To a solution of the thiophene from Table IIb Entry 3 (2.2 g, 5.6 mmol)in DMF in an aluminum foil wrapped round bottom flask under anatmosphere of N₂ was added NBS (2.7 g, 15 mmol). The resultant solutionwas heated to 50° C. with stirring for 8 hours. The solution was cooledto RT. To the solution was added an aqueous solution of NaHCO₃ andNa₂S₂O₅. The aqueous layer was extracted with EtOAc. The organic layerwas washed with sat NaHCO_(3 (aq.)) (2×). The organic layer was driedover Na₂SO₄, filtered and concentrated. The crude product was purifiedvia flash chromatography (SiO₂:gradient elution 100:0 to 83:17hexanes:EtOAc) to afford the bromothiophene (1.7 g, 63% yield).

TABLE VII The following compounds were prepared using a proceduresimilar to that described in Scheme 13 using the appropriate startingmaterial. Entry 2-bromothiophene 1

2

Step 1

To a solution of the thiophene from Scheme 13 (100 mg, 0.21 mmol) in TFA(ca. 2 mL) was added NBS (94 mg, 0.53 mmol) and H₂SO₄ (4 drops). Thesolution was allowed to stir at RT for 30 min. After that time,additional NBS (80 mg) was added and the solution was stirred for anadditional 30 min. The mixture was then quenched with sat. NaHCO₃ (aq.)and Na₂S₂O₅ (s). The aqueous layer was extracted with EtOAc. The organiclayer was washed with sat. NaHCO_(3 (aq.)) (2×), dried over Na₂SO₄,filtered and concentrated. The crude product was slurried in CH₂Cl₂. Tothis mixture was added di-tert-butyldicarbonate (96 mg, 0.21 mmol) andEt₃N (25 mg, 0.23 mmol). The resultant mixture was stirred at RTovernight. The solution was then concentrated and the crude residue waspurified via prep TLC (SiO₂:3:1 hexanes:EtOAc) to afford thedibromothiophene (49 mg).

Step 2

Example 43 was prepared using a method similar to that described inScheme 11b Step 2. LCMS (conditions A): t_(R)=3.07 min, m/e=452.2 (M+H).

Step 1

To a microwave vial containing the thiophene bromide (Scheme 3) (149 mg,0.34 mmol) was added 3-cyano-5-fluorophenyl boronic acid (146 mg, 0.88mmol), 2 M Na₂CO_(3 (aq.)) (0.31 mL) and dioxane (2.5 mL). The mixturewas degassed by bubbling N₂ through it for 5 min. To this mixture wasadded [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with CH₂Cl₂(60 mg, 0.074 mmol). The vial was capped and theatmosphere was purged with nitrogen. The mixture was heated to 60° C.with stirring for 2 hours. The mixture was cooled to RT and diluted withEtOAc. The mixture was then filtered through Celite. The organic layerwas washed with brine. The aqueous layer was back extracted with EtOAc(3×). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated. The crude product was purified via preparative TLC(SiO₂:3:1 hexanes:EtOAc) to afford the biaryl compound (105 mg).

Step 2

To a solution of the biaryl compound from step 1 in CH₂Cl₂ (1.0 mL) wasadded TFA (1.0 mL). The resultant solution was stirred at RT for 1.5hours. The solvent was removed in vacuo to afford Example 44 as thetrifluoroacetate salt. LCMS data: (method A): t_(R)=2.96 min, m/e=379.2(M+H).

TABLE VIII The following examples were prepared using a proceduresimilar to that described in Scheme 15 using the appropriate arylbromide and boronic acid/ester. Examples (LCMS data listed with eachcompound: observed MH⁺, HPLC retention time and LCMS method) 45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

95a

95b

95c

95d

95e

95f

95g

95h

95i

Step 1

To a solution of the thiophene (Scheme 3) (238 mg, 0.54 mmol) inanhydrous THF (2.5 mL) at −78° C. was added a solution of LHMDS (1.0 Min THF, 1.63 mL). The resultant solution was stirred at −78° C. for 1hour. To this solution was added methyl iodide (0.086 mL, 1.36 mmol).The resultant solution was stirred at −78° C. for an additional 1.25hours. After that time, water was added and the mixture was allowed towarm to RT. The aqueous layer was then extracted with EtOAc (3×). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated. The crude product was purified via flashchromatography (SiO₂:gradient elution 100:0 to 80:20 hexanes:EtOAc) toafford the faster eluting trans isomer H (20 mg, 8.1%) and the slowereluting cis isomer I (168 mg, 68%).

Step 2

To a solution of I (16 mg, 0.035 mmol) in CH₂Cl₂ (1 mL) was added TFA (1mL). The resultant solution was stirred at RT for 1.5 hours. Thesolution was concentrated to afford Example 96 (15 mg) as thetrifluoroacetate salt. LCMS data: (method A): t_(R)=2.79 min, m/e=354.2(M+H).

TABLE IX The following examples were prepared using a method similar tothat described in Scheme 16 except NaHMDS was used instead of LHMDS instep 1. LCMS LCMS Ret Obser. time lcms Core Alkyl halide Examples MH⁺(min) method

97

318.1 2.02 B 98

318.0 2.44 B

MeI 99

304.0 1.77 B

100

348.1 2.12 B

MeI 101

369.0 2.16 B

A sealed microwave vial containing a slurry of the thiophene from Scheme13 (74 mg, 0.16 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (19 mg, 0.023 mmol), zinc (8.2mg, 0.12 mmol), zinc cyanide (11 mg, 0.094 mmol) inN,N-dimethylacetamide (2.0 mL) was degassed by bubbling N₂ through themixture for 5 min. The mixture was then heated to 85° C. with stirringfor 2 hours. The mixture was cooled to RT and diluted with Et₂O. Theorganic layer was washed with water (2×), dried over Na₂SO₄, filteredand concentrated. The crude residue was purified by preparative TLC(SiO₂:95:5 CH₂Cl₂:MeOH) to afford Example 102 (15 mg). LCMS data:(method A): t_(R)=2.22 min, m/e=319.2 (M+H).

A 20 mL microwave vessel was flame-dried and cooled under vacuum, thenbackfilled with N₂, followed by two cycles of vacuum/N₂ backfill. Theaniline (Scheme 10) (55 mg, 142 μmol), Pd₂dba₃-CHCl₃ (17 mg, 19 μmol),di-tert-butylphosphinyl-2-biphenyl (15 mg, 50 μmol), sodiumtert-butoxide (31 mg, 322 μmol) and4-bromo-2,2-difluorobenzo[d][1,3]dioxole J (48 mg, 202 μmol) weresuspended in anhydrous toluene (2 mL), the microwave vial was sealed andplaced in a preheated 65° C. oil bath. After stirring for 18 h, thereaction mixture was diluted with EtOAc, washed with sat. aqueous NaHCO₃(1×), dried over MgSO₄, filtered, and concentrated under reducedpressure to give a yellow oil, which was subjected to silica-gelchromatography using 0→20% EtOAc/hexanes as eluent to give intermediateK as a film (39 mg). This intermediate was deprotected with TFA (2 mL)in CH₂Cl₂ (3 mL) at RT, then diluted with toluene (5 mL), concentratedunder reduced pressure, and subjected to RP-HPLC (C18, 30 ml/min,10%-100% MeCN/H₂O) with 0.1% TFA) to give Example 103 in 32% yield (24.9mg, TFA salt). LCMS (conditions C): t_(R)=3.44 min, m/e=443.2 (M+H).

TABLE IXa The following Examples were made using methods described inScheme 18, with the following modification: The coupling reaction wasrun at 80° C.: Examples (LCMS data: observed MH⁺, HPLC retention timeand LCMS method) 103a

MH⁺: 393, 2.01 min, D 103b

MH⁺: 389, 1.88 min, D

Step 1

To a microwave vial containing 3 mL toluene/water (3:1) was added thebromothiophene from Scheme 13 (50 mg, 0.11 mmol), Pd(OAc)₂ (5 mg, 0.02mmol), RuPhos (21 mg, 0.04 mmol), potassium cyclopropyl trifluoroborane(17 mg, 0.12 mmol) and Cs₂CO₃ (108 mg, 0.33 mmol). The vial was sealedand the vial was purged with N₂. The mixture was then heated at 70° C.for 12 hours. Additional Pd(OAc)₂ (5 mg, 0.02 mmol), RuPhos (21 mg, 0.04mmol), potassium cyclopropyl trifluoroborane (17 mg, 0.12 mmol) wereadded and the mixture was heated under an atmosphere of N₂ to 70° C. foran additional 12 hours. The mixture was cooled to RT, filtered throughcelite and extracted with CH₂Cl₂. The aqueous layer was dried overNa₂SO₄, filtered and concentrated. The crude mixture was then dissolvedin CH₂Cl₂. To this solution was added Boc₂O (24 mg, 0.11 mmol) and Et₃N(13 mg, 0.13 mmol). The resultant solution was stirred overnight at RT.The solution was concentrated and the crude product was purified viapreparative TLC (SiO₂; 70:30 hexanes:EtOAc).

Step 2

Example 104 was prepared from the above material using a method similarto that described in Scheme 11b step 2. LCMS data: (method A):t_(R)=2.85 min, m/e=334.2 (M+H).

The biaryl ketone was formed using a method similar to that described inScheme 15 step 1.

TABLE X The following examples were formed using methods similar to thatdescribed in Scheme 1a starting from the ketone in Scheme 20 and theappropriate sulfonamide from Table I. Examples (LCMS data: observed MH⁺,HPLC retention time and LCMS method) 105

MH⁺: 374.9, 2.13 min, B 106

MH⁺: 388.9, 2.22 min, B

TABLE XI The following examples were prepared using a method similar tothat described in Scheme 11b step 2. LCMS LCMS Ret. Obser. time LCMSCarbamate Examples MH⁺ (min) method

107

374.2 2.81 A

108

374.2 2.69 A

Step 1:

To a solution of the bromide (Table IIb, entry 14) (500 mg, 1.11 mmol)in THF (7 mL) at −20° C. was added a solution of MeMgBr (3 M in Et₂O,0.48 mL, 1.4 mmol). The solution was stirred for 30 min at −20° C. Thesolution was then cooled to −78° C. To the solution was added t-BuLi(1.7 M in pentane, 1.6 mL, 2.8 mmol). The solution was stirred for 2 hat −78° C. To the solution was added DMF (0.13 mL, 1.7 mmol). Thesolution was allowed to slowly warm to RT over 2.5 hours. To thesolution was then added sat. NH₄Cl (aq.) (20 mL) and the mixture wasextracted with EtOAc (3×). The combined organic layers were dried overNa₂SO₄, filtered and concentrated. The crude product was purified viaflash chromatography (SiO₂:3:1 heptane:EtOAc) to afford the aldehyde(237 mg, 54%).

To a solution of the aldehyde (1.04 g, 2.60 mmol) in MeOH (10 mL) at 0°C. was added portionwise over 3 min NaBH₄ (197 mg, 5.21 mmol). Theresultant mixture was stirred for 20 min. To the solution was then addedsat. NH₄Cl (aq.) (30 mL) and the mixture was extracted with CH₂Cl₂ (3×).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated. The crude product was purified via flash chromatography(SiO₂:1:1 heptane:EtOAc) to afford the alcohol (949 mg, 91%).

Step 2

To a solution of the alcohol from step 1 (105 mg, 0.26 mmol) andtriphenylphosphine (102 mg, 0.39 mmol) in THF (3 mL) was added3-fluorophenol (0.030 mL, 0.33 mmol). To this solution was addeddropwise DIAD (0.075 mL, 0.39 mmol) and the resultant solution wasstirred for 2 hours. The reaction was loaded onto a SiO₂ flash columnand purified (gradient elution 100:0 to 0:100 heptane:EtOAc) to affordthe ether (73 mg, 56%).

Ex. 109 was prepared from the above material using a method similar tothat described in Scheme 11b step 2. LCMS (conditions B): t_(R)=2.10min, m/e=396.0 (M+H).

TABLE XII The following examples were prepared from the benzylic alcoholdescribed in Scheme 21 step 1 using a method similar to that describedin Scheme 21 step 2 using the appropriate aryl alcohol. Examples (LCMSdata listed with each compound: observed MH⁺, HPLC retention time andLCMS method) 110

MH⁺: 412.0, 2.17 min, B 111

MH⁺: 413.0, 2.02 min, B 112

MH⁺: 397.0, 1.99 min, B 113

MH⁺: 396.0, 2.06 min, B 114

MH⁺: 397.1, 1.96 min, B 115

MH⁺: 412.9, 2.08 min, B

To a stirred solution of the bromide (Table IIb, entry 14, 2.55 g, 5.66mmol) in anhydrous THF (45 mL) was added a MeMgBr solution (3 M in Et₂O,2.4 mL, 7.20 mmol) at −78° C. under nitrogen. After addition wascompleted, the reaction mixture was stirred for 20 min. After that time,a solution of n-BuLi solution (2.5 M in hexanes, 5.1 mL, 12.8 mmol) wasadded dropwise over 5 min. The reaction mixture was then stirred for 50min at −78° C. and the cooling bath was removed. CO₂ gas was bubbledinto the reaction mixture for 50 min. After this time, the reaction wasquenched with saturated aqueous NH₄Cl (50 mL) and 1 N hydrochloric acid(aq) (100 mL). The resulting mixture was extracted with EtOAc (3×100mL). The combined extracts were washed with brine (100 mL), dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography (silica, 10%methanol/methylene chloride) to afford the carboxylic acid (1.49 g,53%).

TABLE XIII The following examples were prepared using a proceduresimilar to that described in Scheme 11b using the acid from Scheme 22and the appropriate aryl amine. The molar ratios used for the acid,amine and BOPCl were 1:1.3:1.5 respectively. Examples (LCMS data:observed MH⁺, HPLC retention time and LCMS method) 116

MH⁺: 459.0, 2.35 min, B 117

MH⁺: 460.1, 2.02 min, B 118

MH⁺: 426.1, 1.86 min, B 119

MH⁺: 410.1, 1.74 min, B

To a sealed round bottom flask containing a solution of the bromide(Table V: Boc intermediate for Ex. 29) (48 mg, 0.084 mmol) in EtOAc (4mL) under an atmosphere of N₂ was added iPr₂NEt (22 μL, 0.13 mmol) and10% Pd/C, Degussa type (9.0 mg, 0.0042 mmol). The flask was evacuatedand backfilled with D₂ (3×). The mixture was stirred under an atmosphereof D₂ for 4.5 hours. The mixture was purged with N₂, filtered andconcentrated. The residue was partitioned between EtOAc and ½ sat.NaHCO₃ (aq.). The aqueous layer was extracted with EtOAc (3×). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated to afford the deuterate (38 mg, 92%) as awhite solid. Example 120 was prepared as its TFA salt from the abovematerial using a procedure similar to that described in Scheme 11b step2. LCMS data: (method D): t_(R)=1.76 min, m/e=393.0 (M+H).

Step 1

To the methyl 5-hydroxypicolinate hydrochloride prepared in scheme 11 h(0.40 g, 2.1 mmol) in DMF (1 mL) was added potassium carbonate (0.88 g,6.3 mmol) and (2-bromoethoxy)-tert-butyldimethylsilane (0.68 mL, 3.2mmol). The reaction was warmed to 70° C. and stirred for 18 h. Anotherequivalent of (2-bromoethoxy)-tert-butyldimethylsilane was added and thereaction stirred for an additional 1.5 h at 90° C. The reaction wascooled to room temperature and water was added. The mixture wasextracted with EtOAc. The combined organic layers were washed with waterand brine, dried (MgSO₄), filtered, and concentrated in vacuo. Theresidue was purified by silica gel chromatography (0-30% EtOAc/hex) over30 minutes to provide product (0.31 g, 47%).

Step 2

To the compound prepared in step 1 (0.31 g, 1.0 mmol) in THF (1.5 mL)was added 2N LiOH (1.5 mL, 3 mmol). The reaction was stirred at roomtemperature for 4 h. The reaction pH was adjusted to pH-4 usingsaturated aqueous citric acid. The mixture was extracted with EtOAc. Thecombined organic layers were washed with water and brine, dried (MgSO₄),filtered, and concentrated in vacuo to provide the carboxylic acid (0.18g, 60%).

Step 3

To the aniline prepared in scheme 10 (0.15 g, 0.39 mmol) in pyridine(1.5 mL) was added the carboxylic acid prepared in step 2 (0.17 g, 0.58mmol) followed by BOP Cl (0.23 g, 0.89 mmol). The reaction was stirredat room temperature for 4.5 h. The reaction was then concentrated invacuo and the residue was taken up into EtOAc and washed with water andbrine, dried (MgSO₄), filtered, and concentrated in vacuo. The residuewas purified by silica gel chromatography (0-30% EtOAc/hex over 30minutes) to provide the amide product (0.14 g, 54%).

Step 4

To the product from step 3 (0.20 g, 0.30 mmol) in THF (1 mL) was addedTBAF (1.0 M in THF, 0.33 mL, 0.33 mmol). The reaction was stirred atroom temperature for 24 h. EtOAc was added to the reaction mixture andthe mixture was washed with water and brine, dried (MgSO₄), filtered,and concentrated in vacuo. The residue was purified by silica gelchromatography (0-70% EtOAc/hex over 30 minutes) to yield the alcohol(0.14 g, 85%).

To that product (0.14 g, 0.25 mmol) in DCM (2 mL) was added TFA (2 mL).The reaction was stirred at room temperature for 1 h and concentrated invacuo. The reaction was then stirred for 1 h with methanol (1 mL) and 7NNH₃/MeOH (0.5 mL). The reaction was then concentrated in vacuo and takenup into EtOAc. The mixture was washed with saturated NaHCO₃, water andbrine, dried (MgSO₄), filtered, and concentrated in vacuo to provideExample 121 (0.10 g, 88%). LCMS data: (method D): t_(R)=1.68 min,m/e=452.0 (M+H).

Step 1

To 2-chloro-5-hydroxypyridine (10 g, 80 mmol) in 1.5 M NaOH_((aq)) (67mL) at 0° C. was added thiophosgene (6.0 mL, 79 mmol) in chloroform (46mL) dropwise. After addition, the reaction was stirred for 2 h. Themixture was then extracted with CHCl₃. The combined CHCl₃ layers werewashed with 1N HCl (aq) and water, dried (MgSO₄), and filtered. Intothis solution was bubbled Cl₂ gas until the reaction became warm (˜1minute). The reaction was stirred at room temperature for 2 h and thenCl₂ gas was bubbled through the mixture again. The reaction was thenstirred for 18 h. Nitrogen gas was then bubbled through the reactionmixture to remove residual Cl₂ gas. The reaction was then concentratedin vacuo. The residue was purified by reverse phase chromatography [C18(800 g) 5% (2 column volumes (CV), 5-100% (10 CV), 100 (2 CV); 0.1%formic acid/water//0.1% formic acid/acetonitrile] to provide thetrichloromethyl ether (4.0 g, 21%).

Step 2

To antimony trifluoride (4.1 g, 22.7 mmol) and antimony pentachloride(0.22 mL, 1.7 mmol) at 120° C. was added the trichloromethyletherprepared in step 1 (2.8 g, 11.3 mmol). The mixture was warmed to 150°C., stirred for 1 h and then cooled to room temperature. DCM andsaturated NaHCO₃ (aq) were added and the aqueous laywer was extractedwith DCM. The combination was washed with 20% KF_((aq)), water andbrine, dried (MgSO₄), filtered, and concentrated in vacuo to provideproduct (2.0 g, 83%).

Step 3

To the chlorodifluoromethylether prepared in step 2 (2.0 g, 9.3 mmol) inpropanenitrile (11 mL) was added bromotrimethylsilane (2.8 mL, 21 mmol).The reaction was warmed to 100° C. and stirred for 6.5 h. The reactionwas cooled to room temperature and saturated NaHCO₃ was added. Themixture was extracted with EtOAc. The combined organics were washed withwater and brine, dried (MgSO₄), filtered, and concentrated in vacuo toprovide a product (2.1 g) which was used in the next step withoutfurther purification.

Step 4

To the bromopyridine prepared in step 3 (0.33 g, 1.3 mmol) in DMF (2.7mL) in a microwave reaction vial was bubbled N₂ gas for 5 minutes.Zn(CN)₂ (0.22 g, 1.9 mmol) was added and nitrogen was bubbled throughthe reaction mixture for 5 minutes. Pd(PPh₃)₄(0.078 g, 0.07 mmol) wasadded and nitrogen was bubbled through the reaction for 5 minutes. Thereaction vessel was capped and warmed to 100° C., then stirred for 2.5 hand cooled to room temperature. Water and EtOAc were added and thecombination was then filtered through a pad of Celite washing withEtOAc. The filtrate was then extracted with EtOAc. The organics werethen combined and washed with water and brine, dried (MgSO₄), filtered,and concentrated in vacuo, then purified by silica gel chromatography(0-8% EtOAc/hex over 30 minutes) to provide product (0.21 g, 81%).

Step 5

To the nitrile prepared in step 4 (0.21 g, 1.0 mmol) in ethanol (2 mL)was added 2N LiOH(aq) (2.7 mL). The reaction was warmed to 100° C. andstirred for 2 h. The reaction was cooled to room temperature and theethanol removed in vacuo. The pH of the aqueous was adjusted to pH-4using saturated aqueous citric acid. Solid sodium chloride was added andthe mixture was extracted with EtOAc. The combined organic layers werewashed with brine, dried (MgSO₄), filtered, and concentrated in vacuo toprovide a white solid (0.14 g, 62%).

Step 6

To the aniline prepared in scheme 10 (0.20 g, 0.52 mmol) in THF (0.84mL) at 0° C. was added the carboxylic acid prepared in step 5 (0.14 g,0.63 mmol), N,N-diisopropylethylamine (0.27 mL, 1.6 mmol), and 50%1-propanephosphonic acid cyclic anhydride in ethyl acetate (0.42 mL,0.71 mmol), respectively. The reaction mixture was then stirred for 1 hat 0° C. and then another hour at room temperature. Water was added tothe reaction and the mixture was stirred vigorously for 20 minutes. Themixture was then extracted with EtOAc. The combined organic layers werewashed with water and brine, dried (MgSO₄), filtered, and concentratedin vacuo. The residue was purified by silica gel chromatography (0-30%EtOAc/hex over 30 minutes) to provide the amide (0.26 g, 84%). To theamide (0.26 g, 0.44 mmol) in DCM (1 mL) at room temperature was addedTFA (0.68 mL, 8.8 mmol). The reaction was stirred for 18 h and thenconcentrated in vacuo. The residue was taken up into DCM and stirredwith saturated NaHCO₃ (aq). The mixture was extracted with DCM. Thecombined DCM layers were washed with water and brine, dried (MgSO₄),filtered, and concentrated in vacuo to provide Example 122. LCMS data:(method D): t_(R)=2.06 min, m/e=492 (M+H).

Step 1

To antimony trifluoride (4.05 g, 23 mmol) and antimony pentachloride(0.22 mL, 1.7 mmol) at 120° C. was added the trichloromethyl etherprepared in step 1 of scheme 25 (2.80 g, 11 mmol). The reaction waswarmed to 165° C. under nitrogen and stirred for 14 h and then warmed to175° C. and stirred for an additional 4 h. The reaction was cooled toroom temperature. The resulting solid mass was stirred vigorously withsaturated NaHCO_(3 (aq.)) [Gas evolution!] and EtOAc. The mixture wasfiltered through a plug of Celite washing with EtOAc. The filtrate wasextracted with EtOAc. The combined organic layers were washed with waterand brine, dried (MgSO₄), filtered, and concentrated in vacuo. Theresidue was purified by silica gel chromatography (0-10% EtOAc/hex over30 minutes) (0.90 g, 40%).

Step 2

The trifluoromethylether prepared in step 1 was converted to thebromopyridine according to the procedure in step 3 of scheme 25.

Step 3

The bromopyridine prepared in step 2 was converted to the cyanopyridineaccording to the procedure in step 4 of scheme 25.

Step 4

The cyanopyridine prepared in step 3 was converted to thepyridylcarboxylic acid according to the procedure in step 5 of scheme25.

Step 5

The pyridylcarboxylic acid prepared in step 4 was converted to Ex. 123according to the procedures in step 6 of scheme 25. LCMS (conditions D):t_(R)=2.04 min, m/e=476.0 (M+H).

Step 1

To the bromothiophene prepared in scheme 13 (1.34 g, 2.83 mmol) in THF(9.2 mL) at 0° C. was added methylmagnesium chloride (3.0 M in THF, 1.18mL, 3.54 mmol). The reaction was stirred for 30 minutes at 0° C. andthen cooled to −78° C. n-Butyllithium (2.5 M in hexanes, 2.55 mL, 6.38mmol) was added over 10 minutes. The reaction was stirred for 1 hour at−78° and then CO₂ gas was bubbled through the reaction. The cold bathwas taken away and the reaction allowed to warm to room temperaturewhile continuing to bubble CO₂ gas through the mixture. To the mixturewas added 1N HCl_((aq.)) and the mixture was extracted with EtOAc. Thecombined organic layers were washed with water and brine, dried (MgSO₄),filtered, and concentrated in vacuo. The residue was purified by silicagel chromatography (0-80% EtOAc/hex over 30 minutes) to provide thecarboxylic acid (0.97 g, 78%).

Step 2

To the carboxylic acid prepared in step 1 (0.027 g, 0.06 mmol) inpyridine (0.25 mL) was added 2-amino-6-methylpyridine (0.013 g, 0.12mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.024 g, 0.09mmol). The reaction was stirred for 18 h at room temperature and thenconcentrated in vacuo. Water was added and the mixture was extractedwith EtOAc. The combined organic layers were washed with brine, dried(MgSO₄), filtered, and concentrated in vacuo. The residue was purifiedby preparative silica gel TLC (1000 μm SiO₂, 30% EtOAc/hexane) toprovide product (13 mg, 40%). To the amide (0.065 g, 0.14 mmol) in DCM(0.4 mL) was added TFA (0.2 mL). The reaction was stirred for 20 h at RTand then concentrated in vacuo to provide Ex. 124 as the TFA salt. LCMSdata: (method D): t_(R)=1.59 min, m/e=428.0 (M+H).

TABLE XIV The following examples were prepared using procedures similarto those described in Scheme 27 using the appropriate aryl amines.Examples (LCMS data: observed MH⁺, HPLC retention time and LCMS method)125 

  MH⁺: 466.0, 1.82 min, D 126 

  MH⁺: 482.0, 2.21 min, D 127 

  MH⁺: 442.0, 1.70 min, D 128 

  MH⁺: 430.0, 1.74 min, D 129 

  MH⁺: 438.0, 1.84 min, D 130 

  MH⁺: 432.0, 1.83 min, D 130a

  MH⁺: 448.0, 1.89 min, D 130b

  MH⁺: 414.0, 1.65 min, D

Step 1:

To the aldehyde (intermediate from scheme 21 step 1 prior to treatmentwith NaBH₄) (0.10 g, 0.2 mmol) in methanol (1.5 mL) and pyridine (0.5mL) was added 4 Å mol sieves (100 mg), 2-amino-5-fluoropyridine (0.056g, 0.5 mmol), and acetic acid (0.02 mL, 0.35 mmol). The reaction waswarmed to 50° C. and stirred for 18 h. After cooling to roomtemperature, saturated sodium bicarbonate (0.5 mL) was added and themixture was stirred for 10 minutes. The mixture was then filtered andthe filtrate was concentrated in vacuo. The residue was purified bysilica gel chromatography (0-35% EtOAc/hex over 30 minutes) to provideproduct (0.077 g, 78%).

Step 2

To the material prepared in step 1 (0.077 g, 0.16 mmol) in DCM (0.4 mL)was added TFA (0.24 mL, 3.1 mmol). The reaction was stirred at roomtemperature for 2 h and then concentrated in vacuo. The residue wastaken up into DCM and washed with saturated NaHCO₃ (aq) water, andbrine. The DCM layer was dried (MgSO₄), filtered, and concentrated invacuo. The residue was then taken up into DCM and excess 2N HCl/etherwas added. The mixture was concentrated to provide Ex. 131 (57 mg) asthe HCl salt. LCMS data: (method D): t_(R)=1.56 min, m/e=396.2 (M+H).

Step 1:

To 7-chloroquinaldine (1.2 g, 6.5 mmol) in THF (80 mL) was addedbis(pinacolato)diboron (1.9 g, 7.6 mmol),1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene hydrochloride (0.17 g,0.4 mmol), and potassium acetate (1.6 g, 16 mmol). Nitrogen was bubbledthrough the reaction for 10 minutes. Palladium acetate (0.044 g, 0.20mmol) was added and the reaction was warmed to reflux and stirred for 6hours. The reaction was filtered through a plug of silica gel washingwith EtOAc. The filtrate was concentrated in vacuo. The filtrate waspurified by silica gel chromatography (0-30% EtOAc/hex over 30 minutes)to provide the boronic ester (0.97 g, 55%).

Step 2

To the boronic ester prepared in step 1 (0.78 g, 2.9 mmol) in THF (6 mL)was added water (24 mL) and sodium metaperiodate (0.93 g, 4.4 mmol). Thereaction was stirred for 1 h and then 3M HCl_((aq)) (19 mL) were added.The mixture was stirred for 45 minutes and then extracted with EtOAc.The aqueous layer was then basified with saturated NaHCO_(3(aq)) andextracted with EtOAc. The organic layer was washed with water and brine,dried (MgSO₄), filtered, and concentrated in vacuo to provide theboronic acid (0.34 g, 63%).

Step 1

To the bromide (Table IIb, entry 14) (0.15 g, 0.33 mmol) in a microwavereaction vial was added t-butanol (1.5 mL),1-(t-butoxycarbonyl)-indole-2-boronic acid (0.16 g, 0.60 mmol) andaqueous potassium carbonate (2M, 0.25 mL, 0.50 mmol). Nitrogen wasbubbled through the reaction mixture for 10 minutes. PdCl₂(dppf) (0.054g, 0.066 mmol) was added and nitrogen was bubbled through the reactionfor 5 minutes. The reaction vessel was capped, warmed to 65° C., andstirred for 3 h. The reaction was cooled to room temperature and EtOAcwas added. The mixture was washed with water and brine, dried (MgSO₄),filtered, and concentrated in vacuo. The residue was purified by silicagel chromatography (0-20% EtOAc/hex over 30 minutes) to provide thebiaryl product (0.12 g, 60%).

Step 2

To the product prepared in step 1 (0.12 g, 0.20 mmol) in DCM (2 mL) wasadded TFA (2 mL). The reaction was stirred at room temperature for 1 hand then concentrated in vacuo to provide Ex. β₂ as a TFA salt (0.078 g,78%). LCMS data: (method D): t_(R)=1.96 min, m/e=387.0 (M+H). Theresidue was further purified as needed by reverse phase chromatography[C18 5% (2 column volumes (CV), 5-100% (10 CV), 100 (2 CV); 0.1% formicacid/water//0.1% formic acid/acetonitrile].

TABLE XV The following examples were prepared using procedures similarto those described in Scheme 30 using the appropriate aryl bromides andboronic acids. Examples (LCMS data: observed MH⁺, HPLC retention timeand LCMS method) 133 

  MH⁺: 417.0, 1.93 min, D 134 

  MH⁺: 401.0, 2.01 min, D 135 

  MH⁺: 412.0, 1.93 min, D 136 

  MH⁺: 421.0, 2.03 min, D 137 

  MH⁺: 420.0, 2.07 min, D 138 

  MH⁺: 435.0, 1.68 min, D 139 

  MH⁺: 409.0, 1.95 min, D 140 

  MH⁺: 428.0, 1.99 min, D 141 

  MH⁺: 439.0, 1.96 min, D 141a

  MH⁺: 443.0, 2.13 min, D ** ** ** **

Step 1:

To 7-azaindole (1.5 g, 12.7 mmol) in DMF (30 mL) at 0° C. was added NaH(60% dispersion in mineral oil, 0.56 g, 14 mmol). The reaction wasstirred for 15 minutes at room temperature then cooled to −40° C.(EtOAc/CO₂ cooling bath). (2-(Chloromethoxy)ethyl) trimethylsilane (2.5mL, 14 mmol) was then added and the reaction allowed to warm to roomtemperature. The reaction was stirred at room temperature for 18 h.EtOAc was added and the mixture was washed with water and brine, dried(MgSO₄), filtered, and concentrated in vacuo. The residue was purifiedby silica gel chromatography (0-10% EtOAc/hex over 30 minutes) toprovide the SEM-protected indole (2.9 g, 91%).

Step 2

To the SEM-protected indole prepared in step 1 (0.99 g, 4.0 mmol) in THF(10 mL) at −40° C. was added n-BuLi (2.5 M in hexanes, 1.9 mL, 4.8mmol). The mixture was stirred at −40° C. for 1 h and then triisopropylborate (1.2 mL, 5.2 mmol) was added. The mixture was allowed to warm toroom temperature while stirring for 18 h. To the reaction mixture wasadded 1N HCl (aq). The mixture was stirred at room temperature for 30minutes. The mixture was then adjusted to pH-5 using saturated NaHCO₃(aq) The mixture was extracted with ether. The combined ether extractswere washed with water and brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The residue was purified by silica gelchromatography (0-50% EtOAc/hex over 30 minutes) to provide the indoleboronic acid (0.20 g, 17%).

Step 3

To the bromide (Table IIb, entry 14) (0.21 g, 0.46 mmol) in t-butanol (3mL) a microwave reaction vial was added the boronic acid prepared instep 2 (0.20 g, 0.68 mmol) and 2M K₂CO_(3 (aq)) (0.34 mL, 0.68 mmol).Nitrogen was bubbled through the reaction for 10 minutes. PdCl₂(dppf)(0.075 g, 0.092 mmol) was added and the reaction was sealed and heatedto 65° C. After 3 h, the reaction was cooled to room temperature andEtOAc was added. The mixture was washed with water and brine (MgSO₄),filtered, and concentrated in vacuo. The residue was purified by silicagel chromatography (0-20% EtOAc/hex over 30 minutes) to provide thecoupling product (0.21 g, 74%).

Step 4

To the coupling product prepared in step 3 (0.086 g, 0.14 mmol) wasadded 4M HCl in ethanol (6 mL). The reaction was warmed to 60° C. andstirred for 20 h. The reaction was concentrated in vacuo and thenpurified by reverse phase chromatography (C18: gradient elution,90:10:0.1 to 0:100:0.1 water:MeCN:formic acid) to provide Ex. 142 (0.030g). LCMS data: (method D): t_(R)=1.67 min, m/e=388.0 (M+H).

Step 1

To the nitropyridine (5.1 g, 30 min) in DMF (5 mL) was added1,1-methoxy-N,N-dimethylmethanamine (15 mL, 110 mmol). The reaction waswarmed to 130° C. and stirred for 16 h. The reaction was cooled to roomtemperature and then added to a beaker of ice. The resulting solid wasisolated by filtration to give product (5.9 g, 88%).

Step 2

To the enamine prepared in step 1 (5.9 g, 26 mmol) in ethanol (275 mL)was added 10% palladium on carbon, Degussa type (1.5 g). The reactionmixture was shaken under a hydrogen atmosphere (15 psi) for 15 minutes.The reaction was filtered through a bed of celite washing with DCM. Thefiltrate was concentrated in vacuo to provide the indole (4.3 g, 61%).

Step 1

The 4-azaindole was protected with the SEM group according to theprocedure described in step 1 of Scheme 31.

Step 2

The SEM protected indole prepared in step 1 was converted to the2-boronic acid according to the procedure described in step 2 of Scheme31.

Step 3

To SEM-protected indole 2-boronic acid prepared in step 2 (0.40 g, 1.37mmol) in a microwave reaction vial in t-butanol (3 mL) was addedpotassium carbonate (2M, 0.6 mL, 1.1 mmol) and the bromothiopheneprepared in scheme 13 (0.36 g, 0.76 mmol). Nitrogen was bubbled throughthe reaction mixture for 10 minutes after which PdCl₂(dppf) (0.12 g,0.15 mmol) was added. The reaction vessel was capped and warmed to 65°C. The reaction was stirred for 16 h and then cooled to roomtemperature. EtOAc was added and the mixture was washed with water andbrine, dried (MgSO₄), filtered, and concentrated in vacuo. The residuewas taken up into DCM (2 mL) and (Boc)₂O (166 mg) was added. Thereaction was stirred at room temperature for 18 h. The reaction wasconcentrated in vacuo to provide a residue that was purified by silicagel chromatography (0-40% EtOAc/hex) to provide a mixture of desiredproduct and bis-boc product (360 mg). The mixture was carried ondirectly to the next step

Step 4:

The biaryl prepared in step 3 (0.28 g, 0.43 mmol) was heated in 4N HClin ethanol (12 mL) to 65° C. for 12 h. The reaction was concentrated invacuo to provide desired material and the indole N-hydroxymethylintermediate. The mixture was taken up into acetone (2 mL) and ethanol(1 mL) and potassium carbonate was added (0.15 g, 1.1 mmol). The mixturewas stirred at room temperature for 1 h and then added to saturatedNH₄Cl_((aq)). The mixture was extracted with EtOAc. The combined organiclayers were washed with water and brine, dried (MgSO₄), filtered, andconcentrated in vacuo. The residue was purified by preparative silicagel TLC (10% MeOH/DCM) to provide Ex. 143 (0.10 g, 57%). LCMS data:(method D): t_(R)=1.67 min, m/e=410.0 (M+H). (Alternatively, the residuecould be purified by reverse phase chromatography [C18 5% (2 columnvolumes (CV), 5-100% (10 CV), 100 (2 CV); 0.1% formic acid/water//0.1%formic acid/acetonitrile]).

TABLE XVI Using the conditions described in Scheme 33, the followingexamples were prepared from the appropriate aryl bromides and arylboronic acids. Examples (LCMS data: observed MH⁺, HPLC retention timeand LCMS method) 144

  MH⁺: 440.0, 1.65 min, D 145

  MH⁺: 410.0, 1.78 min, D 146

  MH⁺: 410.0, 1.70 min, D 147

  MH⁺: 410.0, 1.67 min, D

Step 1

To a slurry of the aniline from Scheme 10a (95 mg, 0.20 mmol), picolinicacid (30 mg, 0.25 mmol) and BOPCl (78 mg, 0.31 mmol) in CH₂Cl₂ (4 mL) at0° C. was added iPr₂NEt (89 μL, 0.51 mmol). The resultant mixture waswarmed to RT and stirred for 16 hours. The mixture was partitionedbetween CH₂Cl₂ and water. The aqueous layer was extracted with CH₂Cl₂(3×). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated. The crude product was purified via preparative TLC(SiO₂:1:1 hexanes:EtOAc) to afford the amide (47 mg, 40%) as a whitesolid.

Step 2

Ex. 148 was prepared as its TFA salt from the above material using aprocedure similar to that described in Scheme 23. LCMS data: (method D):t_(R)=1.75 min, m/e=393.0 (M+H).

Step 1

To a RT mixture of aniline (Scheme 10, 0.1 g, 0.26 mmol), 2 mL DCM,diisopropylethylamine (45 μL, 0.26 mmol), and trifluoroacetophenone(0.045 g, 0.26 mmol) was slowly added dropwise titanium tetrachloride(1.0 M in DCM, 0.26 mL, 0.26 mmol). The reaction was stirred for 2hours. Saturated aqueous sodium bicarbonate was then poured into thereaction, forming a white precipitate, which was then filtered throughcelite. The celite was washed with DCM and the filtrate was extractedwith DCM. The combined organic layers were dried (MgSO₄), filtered, andconcentrated in vacuo. The residue was purified by silica gelchromatography (0-30% EtOAc/hexanes over 20 minutes) to provide theimine compound (0.051 g, 36%).

Step 2

To the imine prepared in Step 1 (0.051 g, 0.09 mmol) stirring in 2 mLMeOH was added sodium borohydride (0.007 g, 0.18 mmol). The reaction wasstirred at room temperature for 1 hour, then concentrated to dryness invacuo. The reaction was purified by preparative RP HPLC (10-100%acetonitrile with 0.1% formic acid/water with 0.1% formic acid over 22minutes) to provide the amine product. This material was treated with 2mL 20% TFA/DCM for 1 hour, and then concentrated in vacuo to provideExample 149 (1:1 mixture of diastereomers) as a trifluoroacetate salt(39 mg, 75%). LCMS data: (method D): t_(R)=1.97 min, m/e=445.0 (M+H).

TABLE XVII The following examples were made according to the methodsdescribed in Scheme 35: Examples (LCMS data: observed MH⁺, HPLCretention time and LCMS method) 150

  MH⁺: 446.0, 1.87 min, D 151

  MH⁺: 464.0, 1.93 min, D 152

  MH⁺: 514.0, 1.99 min, D 153

  MH⁺: 451.0, 1.93 min, D

TABLE XVIII The following Example was made as a mixture of diastereomersusing the following sequence: (1) Scheme 35, Step 1, (2) Scheme 11b,Step 2: Example (LCMS data: observed MH⁺, HPLC retention time and LCMSmethod) 154

  MH⁺: 395.0, 1.89 min, D

Step 1

To the aniline (Table IV, entry 5 0.2 g, 0.5 mmol) stirring at roomtemperature in glacial acetic acid (5 mL) was added dropwise a solutionof sodium nitrite (0.035 g, 0.5 mmol) in water (0.25 mL). The reactionwas stirred at room temperature 6 hrs, then concentrated to dryness invacuo. The residue was purified by silica gel chromatography (0-100%EtOAc/hexanes over 30 minutes) to provide the indazole compound as asolid (0.060 g, 29%).

Step 2

The material from step 1 (0.005 g, 0.012 mmol) was treated according toScheme 11b, step 2 to afford Example 155 as the TFA salt (0.005 g, 97%).LCMS data: (method D): t_(R)=1.63 min, m/e=312.0 (M+H).

To the aminopyridine compound (Table IIb, 0.068 g, 0.17 mmol) stirringin 1.68 mL 4:1 DMF:diisopropylethylamine at room temperature was added5-chloropicolinoyl chloride (Scheme 11p) and 1 crystal of DMAP. Thereaction was heated to 50° C. and stirred for 48 hours. The reaction wascooled to room temperature and concentrated in vacuo. The residue waspurified by silica gel chromatography (0-60% EtOAc/hexanes over 20minutes, then 60-100% EtOAc/hexanes 20-30 minutes) to provide an amideproduct (0.014 g, 15%). This material was treated according to Scheme11b, step 2 to provide Example 156 (0.014 g, 97%) as a trifluoroacetatesalt. LCMS data: (method D): t_(R)=1.91 min, m/e=443.0 (M+H).

TABLE XIX The following examples were made according to the methodsdescribed in Scheme 37 using acid chlorides from Table IVj: Examples(LCMS data: observed MH⁺, HPLC retention time and LCMS method) 157

  MH⁺: 477.0, 1.93 min, D 158

  MH⁺: 440.0, 1.84 min, D

To Example 154 (0.020 g, 0.04 mmol) stirring in 2 mL EtOH was added 10%palladium on carbon (0.010 g). This solution was subjected to a hydrogenatmosphere (balloon) and stirred 16 hours. The reaction was filteredthrough celite and washed with MeOH. The filtrate was concentrated todryness in vacuo and purified by preparative RP HPLC (10-100%acetonitrile with 0.1% formic acid/water with 0.1% formic acid over 22minutes) to provide Example 159 as a mixture of diastereomers as aformate salt (0.013 g, 65%). LCMS data: (method D): t_(R)=1.92 min,m/e=397.0 (M+H).

Step 1

To the aniline (Scheme 10, 0.1 g, 0.26 mmol) stirring in 3 mL DCM wasadded triethylamine (54 μL, 0.39 mmol) and 1-piperidinecarbonyl chloride(34 μL, 0.27 mmol), and the mixture was allowed to stir for 3 days atroom temperature. The reaction was poured into water and extracted withDCM. The combined organic layers were dried (MgSO₄), filtered, andconcentrated in vacuo. The residue was purified by silica gelchromatography (0-80% EtOAc/hexanes over 20 minutes) to provide a ureaproduct (0.093 g, 72%). This compound was then treated according toScheme 11b, Step 2 to provide Example 160 (0.094 g, 98%) as atrifluoroacetate salt. LCMS data: (method D): t_(R)=1.75 min, m/e=398.2(M+H).

TABLE XX The following examples were made according to the methodsdescribed in Scheme 39 using the appropriate carbonl chloride: Example(LCMS data: observed MH⁺, HPLC retention time and LCMS method) 161 

  MH⁺: 384.2, 1.61 min, D 161a

  MH⁺: 400.0, 1.47 min, D

The bromopyridine compound (Scheme 7a, step 6) 0.07 g, 0.16 mmol) alongwith O-anisidine (22 μL, 0.19 mmol),tris(dibenzylideneacetone)dipalladium (0.003 g, 0.003 mmol), racemic2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.004 g, 0.006 mmol), andsodium t-butoxide (0.022 g, 0.22 mmol) were stirred in a flame-dried,sealed microwave vial flushed with nitrogen in 2 mL anhydrous toluene at80° C. for 3.5 hours. The reaction mixture was cooled to roomtemperature, poured into water, and extracted with DCM. The combinedorganic layers were dried (MgSO₄), filtered, and concentrated in vacuo.The residue was purified by silica gel chromatography (0-60%EtOAc/hexanes over 20 minutes) to provide biarylamine product (0.007 g,9%). This material was treated according to Scheme 11b, Step 2 toprovide Example 162 as a trifluoroacetate salt (0.007 g, 97%). LCMSdata: (method D): t_(R) 1.80 min, m/e=376.2 (M III).

TABLE XXI The following Examples were made according to the methods inScheme 40: Examples (LCMS data: observed MH⁺, HPLC retention time andLCMS method) 163

  MH⁺: 426.0, 2.05 min, D 164

  MH⁺: 372.0, 1.83 min, D 165

  MH⁺: 377.0, 1.65 min, D 166

  MH⁺: 377.0, 1.18 min, D 167

  MH⁺: 376.0, 1.38 min, D **

The aniline shown (Scheme 10) was treated according to Scheme 11b using5-cyclopropylpyrazine-2-carboxylic acid (Table IVg, entry 4) to afford,after separation, both Example 169 [LCMS data: (method D): t_(R)=1.80min, m/e=433.0 (M+H)] and Example 168 [LCMS data: (method D): t_(R)=1.83min, m/e=469.0 (M+H)] both as TFA salts.

The aniline shown (Scheme 10) was treated according to Scheme 11b using3,5-dimethoxypyridine-2-carboxylic acid (Scheme 11q) to afford, afterseparation, both Example 170 [LCMS data: (method D): t_(R)=1.73 min,m/e=452.0 (M+H)] and Example 171 [LCMS data: (method D): t_(R)=1.85 min,m/e=438.0 (M+H)] both as TFA salts.

Step 1

To a −40° C. mixture of concentrated H₂SO₄ (100 mL) and fuming HNO₃ (100mL) was added 1-(2,6-difluorophenyl)ethanone (20 g, 128 mmol) dropwise.The resulting mixture was stirred at −40° C. for 2 h then poured slowlyonto ice. That mixture was diluted with DCM and the phases wereseparated. The aqueous layer was neutralized with sat. aq. NaHCO₃ andthen extracted with DCM. All organic portions were combined, dried overMgSO₄, filtered, and concentrated to give1-(2,6-difluoro-3-nitrophenyl)ethanone (26.3 g, 131 mmol, >theoretical)that was used without further purification.

Step 2

The nitrophenyl ketone from the previous step was treated according toScheme 1a, Step 1 [substituting (S)-2-methyl-2-propanesulfinamide for(R)-2-methyl-2-propanesulfinamide] to give a ketimine product (17.1 g,44% based on 1-(2,6-difluorophenyl)ethanone from Step 1).

Step 3

The ketimine from step 2 (17.1 g, 56.2 mmol) was treated according toScheme 1a, Step 3 to give desired syn addition product (6 g, 20%) aswell as a mixture of syn and anti diastereomers (6 g, 3:1, 20%).

Step 4

To a solution of the syn addition product from Step 3 (2.71 g, 5.1 mmol)in 25 mL of ethanol was added 10% Pd/C (298 mg). The mixture was placedunder H₂ balloon atmosphere overnight. After filtration through Celite,the filtrate was concentrated. The crude residue was purified by flashsilica column (60%-100% EtOAc/hexanes) to give the aniline product (1.75g, 68% yield).

Step 5

A mixture of the aniline from Step 4 (453 mg, 0.9 mmol),3,5-difluoropicolinic acid (215 mg, 1.4 mmol), and BOPCl (527 mg, 2.07mmol) in 4 mL of pyridine was stirred overnight. After it was quenchedwith 1N HCl (aq), the mixture was extracted with ethyl acetate. Theorganic portions were combined, dried over MgSO₄ and concentrated. Thecrude residue was purified by flash silica column (40% EtOAc/hexane) togive an amide product (431 mg, 74% yield).

Step 6

To a solution of the above material (431 mg, 0.67 mmol) in 3 mL of DCMand 1 mL of methanol was added 4N HCl in dioxane (1 mL, 4.0 mmol). Afterthe mixture was stirred for 1 h, it was concentrated. This sample wastreated with a mixture of TFA (4 mL) and thioglycolic acid (0.46 mL, 6.7mmol). After the mixture was stirred for 4 h, it was concentrated. Thecrude residue was neutralized by carefully adding saturated sodiumbicarbonate solution. The resulting mixture was extracted with ethylacetate, the organic portions were combined, dried over magnesiumsulfate, and concentrated to an amine product that was used in thesubsequent step without further purification.

Step 7

To the material from step 6 (assumed to be 0.67 mmol) in 5 mL of DCM wasadded benzoyl isothiocyanate (0.12 mL, 0.87 mmol). The mixture wasstirred overnight at RT. After it was concentrated, the residue wasdissolved in 5 mL of methanol, and sodium methoxide (25% in methanol,0.37 mL) was added. The mixture was stirred for 2 h at RT. It wasquenched with 2 drops of acetic acid. After the mixture wasconcentrated, the crude was diluted with saturated sodium carbonate, andextracted with DCM. The combined organic portions were dried overmagnesium sulfate and concentrated to give an isothiourea product thatwas used in the subsequent step without purification.

Step 8

To a solution of the material from step 7 (assumed to be 0.67 mmol) in 5mL of ethanol was added methyl iodide (0.05 mL, 0.8 mmol). The mixturewas stirred overnight at room temperature and then diluted withsaturated sodium bicarbonate. After the mixture was extracted with ethylacetate, the organic layers were combined, dried over magnesium sulfate,and concentrated. The crude residue was dissolved in 5 mL of ethanol,and the mixture was heated at 50° C. for 2 h. The mixture was thendiluted with saturated sodium bicarbonate, and extracted with ethylacetate. The organic portions were combined, dried over magnesiumsulfate, and concentrated. The crude residue was purified by reversephase HPLC (C18 radial compression, 10% to 100% MeCN/water with 0.1%TFA) to give Example 172 as a TFA salt (40.3 mg, 14% from the product ofStep 5). LCMS (conditions A): t_(R)=2.43 min, m/e=458.3 (M+H).

TABLE XXII The following examples were made from1-(2,6-difluorophenyl)ethanone using methods similar to those describedin Scheme 43, substituting the appropriate acid in Step 5: Examples(LCMS data: observed MH⁺, HPLC retention time and LCMS method) 173

  MH⁺: 428.2, 2.46 min, A 174

  MH⁺: 442.2, 3.17 min, A

Steps 1-4:1-(5-Methyl-4-nitrothiophen-2-yl)ethanone, obtained bynitration from 1-(5-methylthiophen-2-yl)ethanone according to theliterature procedure (E. Campaigne, J. L. Diedrich, J. Am. Chem. Soc.1951, 73, 5240-5243), was converted into the product of step 4 usingsimilar procedures in the following sequence: (i) Scheme 1a, steps 1-4,(ii) Scheme 3b.

Step 5

To a solution of the product of step 4 (570 mg, 1.37 mmol) in MeOH (25mL) was added 10% Pd(OH)₂/C (250 mg), and the reaction was stirred in aParr-shaker under an atmosphere of H₂ (50 psi) for 18 h. The reactionwas filtered over a pad of celite, the filter residue rinsed with MeOHand the combined organic layers concentrated under reduced pressure togive a residue (423 mg, 80%). To a solution of this residue (423 mg,1.08 mmol) in toluene (3 mL) was added KOAc (85 mg, 0.86 mmol), aceticanhydride (0.205 mL, 2.16 mmol) and tert-butylnitrite (0.145 mL, 1.2mmol). The reaction was stirred at 90° C. for 4.5 h, then cooled to RTand diluted with EtOAc. After filtration through celite, the filtratewas concentrated under reduced pressure to give a residue that wassubjected to silica gel chromatography (gradient elution 100:0 to 70:30hexanes:EtOAc). The resulting mixture of acetylated and deacetylatedmaterials (298 mg) was dissolved in THF (5 mL) and treated with aqueous1 M LiOH (2 mL) for 30 min at RT. The reaction was diluted with EtOAc,the layers separated and the aqueous layer extracted with EtOAc (1×).The combined organic layers were washed with brine, dried over MgSO₄,and concentrated under vacuum to give the product of step 5 (282 mg,65%).

Step 6

Sodium hydride (60% in mineral oil, 20 Ing, 0.5 mmol) was added to asolution of the product from step 5 (78 mg, 0.195 mmol) in DMF (2 mL) atRT. After 5 min, 2-fluoro-5-bromopyridine (54 mg, 0.306 mmol) was addedand the reaction stirred for 19 h at RT, then quenched with water andEtOAc. The organic layer was washed with saturated aqueousNaHCO_(3 (aq.)), brine, and then dried over MgSO₄, and concentratedunder vacuum. To a solution of this residue in MeOH was added 10%Pd(OH)₂/C (110 mg), and the reaction was stirred under aballoon-atmosphere of H₂ for 72 h. The catalyst was removed byfiltration over celite, and the filtrate concentrated under reducedpressure to give a mixture of regioisomeric intermediates that wereseparated by silica gel chromatography (gradient elution withhexanes:EtOAc). Each regioisomer was deprotected according to theprocedure described in Scheme 11 b, Step 2, then subjected to reversephase chromatography (C18: gradient elution, 90:10:0.1 to 0:100:0.1water:MeCN:TFA) to provide Example 175 and Example 176 as their TFAsalts. LCMS for Ex. 175 (conditions D): t_(R)=1.80 min, m/e=377.0 (M+H);LCMS for Ex. 176 (conditions D): t_(R)=1.78 min, m/e=377.0 (M+H).

TABLE XXIII The following examples were prepared using a proceduresimilar to that described in Scheme 44 omitting the hydrogenationportion of step 6. Example 177

  MH⁺: 455.0, 1.92 min, D

Step 1:

To a −78° C. solution of 1-phenyl-H-thieno[3,2-c]pyrazole (1.94 g, 9.68mmol), obtained from 3-bromothiophene-2-carbaldehyde according to theliterature procedure (Lebedev et al., J. Org. Chem. 2005, 70, 596-602),was added nBuLi (4.25 mL of a 2.5 M solution in hexanes, 10.65 mmol)over 5 min. After 30 min at −78° C., N-acetylmorpholine (2.3 mL, 20mmol) was added and the reaction was stirred for 60 min at −78° C., thenstirred for 6 h while slowly warming to RT. The reaction was quenchedwith saturated aqueous NH₄Cl and diluted with EtOAc. The organic layerwas washed with sat. aqueous NaHCO₃ and brine, dried over MgSO₄ andconcentrated under reduced pressure. The residue was subjected to silicagel chromatography (gradient elution 100:0 to 85:15 hexanes:EtOAc) togive 1-(1-phenyl-1H-thieno[3,2-c]pyrazol-5-yl)ethanone (682 mg, 2.81mmol, 29%) along with recovered starting material (823 mg, 4.13 mmol,43%).

Steps 2-5:

These steps were performed using similar procedures to the followingsequence: (i) Scheme 1a, steps 1-4, (ii) Scheme 3b, omitting thecoversion to the t-butyl carbamate. The final intermediate was subjectedto reverse phase chromatography (C18: gradient elution, 90:10:0.1 to0:100:0.1 water:MeCN:TFA) to provide Ex. 178 as its TFA salt. LCMS forEx. 178 (conditions D): t_(R)=1.82 min, m/e=376.0 (M+H).

Step 1

CuI (7.6 mg, 0.04 mmol) was added to a solution of iodoaniline (200 mg,0.39 mmol, Scheme 10a), diisopropylamine (0.169 mL, 1.2 mmol),PdCl₂(PPh₃)₂ (28 mg, 0.04 mmol) and phenyl acetylene (0.132 mL, 1.2mmol) in dimethylacetamide (2 mL), and the reaction was stirred at 40°C. for 6 h. The reaction was diluted with sat. aqueous NaHCO₃ solutionand EtOAc, then filtered reaction over celite. After rinsing the residuewith EtOAc, the aqueous layer was extracted with EtOAc (3×). Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated to give a residue that was subsequently subjected to silicagel chromatography (10→20% EtOAc/hexanes) to provide the anilinoacetylene intermediate (181 mg, 95%).

Step 2

Trifluoroacetic acid (0.2 mL) was added to a solution of the productfrom step 1 (181 mg, 0.37 mmol) in DCM (1 mL) at RT. After 2 h, thereaction was concentrated under vacuum. To part of the residue (50 mg,0.13 mmol) in toluene (1 mL) was added InBr₃ (46 mg, 0.13 mmol.), andthe reaction was heated to 115° C. for 2 h. After removing volatilesunder reduced pressure, the residue was suspended in MeOH, filteredthrough a PTFE-filter and the filtrate subjected to reverse phasechromatography (C18: gradient elution, 90:10:0.1 to 0:100:0.1water:MeCN:TFA) to provide Ex. 179 as its TFA salt (11.7 mg, 30%). LCMSfor Ex. 179 (conditions D): t_(R)=1.98 min, m/e=387.2 (M+H).

Step 1

The anilino acetylene intermediate was prepared in the same manner as inScheme 46, Step 1 except that isoproylacetylene was used instead ofphenylacetylene.

Step 2

To the anilino acetylene intermediate from Step 1 (100 mg, 0.22 mmol) inEtOH (1 mL) was added AuCl₃ (133 mg, 0.44 mmol), and the reaction washeated to 70° C. for 3 h. After removing volatiles under reducedpressure, the residue was suspended in MeOH, filtered through aPTFE-filter and the filtrate subjected to reverse phase chromatography(C18: gradient elution, 90:10:0.1 to 0:100:0.1 water:MeCN:TFA) toprovide Example 180 as its TFA salt (17.2 mg, 20%). LCMS for Example 180(conditions D): t_(R)=2.04 min, m/e=387.0 (M+H).

Step 1

The anilino acetylene intermediate was prepared in the same manner as inScheme 46, Step 1 except that cycloproylacetylene was used instead ofphenylacetylene.

Step 2

To the anilino acetylene intermediate from Step 1 (54 mg, 0.11 mmol) inNMP (1 mL) was added potassium tert-butoxide (37 mg, 0.33 mmol), and thereaction was stirred for 18 h at RT. The mixture was then diluted withwater and EtOAc, the organic layer was dried over Na₂SO₄, filtered, andconcentrated to give a residue that was subsequently subjected to silicagel chromatography (10→25% EtOAc/hexanes) to provide the Boc-protectedindole intermediate (35 mg, 70%). This intermediate was deprotectedaccording to the procedure described in Scheme IIb, Step 2, thensubjected to reverse phase chromatography (C₁₈: gradient elution,90:10:0.1 to 0:100:0.1 water:MeCN:TFA) to provide Ex. 181 as its TFAsalt. LCMS for Ex. 181 (conditions D): t_(R)=1.91 min, m/e=351.2 (M+H).

TABLE XXIV The following examples were prepared using a proceduresimilar to that described in Schemes 46, 47 and 48. Examples (LCMS data:observed MH⁺, HPLC retention time and LCMS method) 182

  MH⁺: 421.2, 2.07 min, D 183

  MH⁺: 353.2, 1.96 min, D 184

  MH⁺: 401.2, 2.01 min, D 185

  MH⁺: 353.0, 1.98 min, D 186

  MH⁺: 325.0, 1.85 min, D 187

  MH⁺: 388.0, 1.74 min, D 188

  MH⁺: 367.0, 2.02 min, D 189

  MH⁺: 339.0, 1.87 min, D

Step 1:

Trifluoroacetic anhydride (2.34 mL, 16.85 mmol) was added dropwise to asolution of aniline (5.5 g, 14.24 mmol, Scheme 10) and triethylamine(2.39 mL, 17.1 mmol) in DCM (30 mL) at 0° C. After stirring at RT for 2h, the reaction was quenched with saturated aqueous NaHCO₃ and dilutedwith EtOAc. The organic layer was dried over Na₂SO₄ and concentratedunder reduced pressure to give a solid (6.0 g), which was dissolved inDCM (10 mL) and stirred with TFA (2 mL) for 1 h at RT. The reaction wasconcentrated under reduced pressure, and the residue dissolved inconcentrated H₂SO₄ (9 mL). After cooling to 0° C., a mixture of fumingHNO₃/conc. H₂SO₄ (1.26 mL/3 mL) was slowly added via addition funnel.After 40 min, the reaction was carefully quenched with saturated aqueousNaHCO₃ and diluted with EtOAc. The aqueous layer was extracted withEtOAc (3×), and the combined organic layers were dried over Na₂SO₄, andconcentrated under reduced pressure. The resulting residue was dissolvedin DCM (100 mL), and triethylamine (7.93 mL, 56.56 mmol) anddi-tert-butylcarbonate (3.09 g, 28.28 mmol) were added. After stirringfor 18 h at RT, the reaction was quenched with saturated aqueous NH₄Cland diluted with EtOAc. The organic layer was dried over Na₂SO₄,concentrated under reduced pressure, and the resulting residue wassubjected to silica gel chromatography (gradient elution 80:20 to 75:25hexanes:EtOAc) to give a mixture of acetylated and deacetylatedmaterial. To a solution of this mixture in MeOH (100 mL) at RT was addeda solution of K₂CO₃ (5 g, 36 mmol) in water (20 mL), and the reactionstirred for 2 h at RT. The reaction was quenched with 1 M HCl (aq) anddiluted with EtOAc. The organic layer was dried over Na₂SO₄, andconcentrated under reduced pressure to give product (3.3 g, 54%).

Step 2

To a solution of the product from step 1 (600 mg, 1.39 mmol) inEtOAc/EtOH (10 mL/10 mL) was added 5% Pd/C (300 mg) and the resultingmixture agitated in a Parr Shaker for 4 h under a 45-psi atmosphere ofHz. The catalyst was filtered off over celite, the residue rinsed withEtOAc, and the organic layer was concentrated under reduced pressure.The resulting residue was subjected to silica gel chromatography(gradient elution 95:5 to 90:10 hexanes:EtOAc) to give product (377 mg,68%).

Step 3

To a solution of the product from step 2 (150 mg, 0.37 mmol) in pyridine(3 mL) was added 3,3,3-trifluoropropionic acid (0.032 mL, 0.37 mmol) andbis(2-oxo-3-oxazolidinyl)phosphinic chloride (188 mg, 0.74 mmol). Afterstirring for 18 h at RT, the volatiles were removed under vacuum, andthe residue was subjected to silica gel chromatography (gradient elution60:40 to 30:70 hexanes:EtOAc) to give a mixture of amides (102 mg, 54%).This mixture was dissolved in glacial AcOH (2 mL) and heated to 130° C.for 1 h. The volatiles were removed under reduced pressure, and theresulting residue purified by reverse phase chromatography (C18:gradient elution, 90:10:0.1 to 0:100:0.1 water:MeCN:TFA) to provide Ex.190 as its TFA salt. LCMS for Ex. 190 (conditions D): t_(R)=1.29 min,m/e=394.2 (M+H).

TABLE XXV The following examples were prepared using a procedure similarto that described in Scheme 49. Examples (LCMS data: observed MH⁺, HPLCretention time and LCMS method) 191

  MH⁺: 380.2, 1.10 min, D 192

  MH⁺: 403.2, 1.18 min, D 193

  MH⁺: 366.2, 1.18 min, D 194

  MH⁺: 354.0, 0.97 min, D 195

  MH⁺: 368.0, 1.44 min, D

Step 1

Thiophosgene (0.320 mL, 4.21 mmol) was slowly added to a biphasicmixture of saturated aqueous NaHCO₃ and a solution of dianiline (1.566g, 3.90 mmol, Scheme 49, Step 2) in DCM (15 mL). After 1 h at RT, thephases were separated and the aqueous layer extracted with DCM. Thecombined organic layers were washed with saturated aqueous NaHCO₃,brine, then dried over Na₂SO₄, filtered and concentrated under reducedpressure to give the thiourea (1.604 g, 93%).

Step 2

Potassium carbonate (750 mg, 5.43 mmol) was added to a solution of thethiourea from Step 1 (1.604 g, 3.62 mmol) in DMF (18 mL) at RT. After 10min, a solution of methyl iodide (0.23 mL, 3.68 mmol) in DMF (2 mL) wasadded over 10 min, and the reaction was stirred for 90 min. The reactionwas quenched with saturated aqueous NaHCO₃ and diluted with EtOAc, andthe organic layer was washed with brine, dried over MgSO₄ andconcentrated under reduced pressure (1.725 g). The residue was subjectedto silica gel chromatography (gradient elution 100:0 to 60:40hexanes:EtOAc) to give the thiomethylurea (846 mg, 51%).

Step 3

Meta-chloroperoxybenzoic acid (72%, 150 mg, 0.63 mmol) was added at RTto a solution of the thiomethylurea from step 2 (100 mg, 0.21 mmol) inDCM (5 mL). After 1 h, the mixture was diluted with EtOAc and washedwith saturated aqueous NaHCO₃ (2×), brine, and dried over MgSO₄ andconcentrated under reduced pressure to give a residue (150 mg) that wasfurther subjected to reverse phase chromatography (C18: gradientelution, 90:10:0.1 to 0:100:0.1 water:MeCN:TFA) to provide Ex. 196 asits TFA salt. LCMS for Ex. 196 (conditions D): t_(R)=1.41 min, m/e=390.0(M+H).

Step 1

A solution of oxone (potassium peroxymonosulfate, 3.2 g, 5.20 mmol) inwater (10 mL) was added at RT to a solution of the thiomethylurea fromScheme 50, step 2 (755 mg, 1.65 mmol) in MeOH (10 mL). After 1 h, themixture was filtered over celite, the filter cake rinsed with EtOAc, andthe filtrate diluted with EtOAc. The combined organic layers were washedwith saturated aqueous NaHCO₃, dried over MgSO₄ and concentrated underreduced pressure to give the intermediate (681 mg) in 84% yield.

Step 2

The product of Step 1 (93 mg, 0.19 mmol) was deprotected using a methodsimilar to that described in Scheme 11b step 2. After deprotection, theresulting residue was concentrated under vacuum, and triethylamine(0.132 mL, 0.95 mmol) and phenol (90 mg, 0.95 mmol) were added. Themixture was heated at 120° C. for 22 h, then cooled to RT. The residuewas subjected to reverse phase chromatography (C18: gradient elution,90:10:0.1 to 0:100:0.1 water:MeCN:TFA) to provide Ex. 197 as its TFAsalt. LCMS for Ex. 197 (conditions D): t_(R)=1.78 min, m/e=404.2 (M+H).

TABLE XXVI The following examples were prepared using a proceduresimilar to that described in Scheme 51, replacing phenol in Step 2 withthiophenol or aniline, respectively. Examples (LCMS data listed witheach compound: observed MH⁺, HPLC retention time and LCMS method) 198

  MH⁺: 420.0, 1.76 min, D 199

  MH⁺: 403.2, 1.64 min, D

Step 1

To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.53 g, 10.0mmol) in 30 mL of THF was added NaH (560 mg, 14.0 mmol, 60% in mineraloil) by portion under N₂. After the mixture was cooled to 0° C., benzylchloromethyl ether (1.71 mL, 13.0 mmol) was added. Then the mixture wasstirred at RT for 1 h (monitored by TLC 40% EtOAc/Hex). 8 mL ofanhydrous MeOH was added into the reaction mixture followed by NaH (400mg, 10.0 mmol, 60% mineral oil) by portion. The resulting mixture wasstirred at RT overnight. After being quenched with sat. NH₄Cl, themixture was extracted with EtOAc (3×). The organic layer was washed withsat.NaHCO₃ (aq), brine, then dried (MgSO₄) and concentrated. Silica gelchromatography (elution with 0-30% EtOAc/Hex) afforded product5-(benzyloxymethyl)-4-methoxy-5H-pyrrolo[3,2-d]pyrimidine (2.36 g).

Step 2 and 3:

5-(Benzyloxymethyl)-4-methoxy-5H-pyrrolo[3,2-d]pyrimidine was treatedaccording to Scheme 31, Steps 2 and 3 to afford a biaryl product.

Step 4

To a solution of the material from step 3 (26 mg, 0.039 mmol) in 8 mL ofDCM was added a suspension of AlCl₃ (52 mg, 0.39 mmol) in 4 mL of DCM.After the mixture was stirred at RT for 1.5 h, 3 mL of water was added.The reaction mixture was basified with NaHCO₃ and extracted with DCM(3×). The organic layer was washed with brine and dried (Na₂SO₄), andconcentrated. The crude residue was purified by preparative TLC (10% 2NNH₃ MeOH in DCM) to provide Example 200 (10 mg). LCMS (conditions E):t_(R)=0.60 min, m/e=441.0 (M+H).

Step 1

The aniline from Scheme 10 and the acid (Entry 3, Table IVb) werecoupled using a procedure similar to that described in Scheme 11b step1.

Step 2

To a pressure vessel containing a solution of the amide from step 1 (181mg, 0.28 mmol) in EtOH (15 mL) was added 10% Pd/C (50% water-DegussaType). The vessel was sealed, evacuated and backfilled with N₂ (3×). Thevessel was then evacuated and backfilled with H₂ (3×). The vessel waspressurized with H₂ to 50 psi and shaken at RT for 6 hours. The mixturewas purged with N₂, filtered through Celite and concentrated. The crudeproduct was purified via flash chromatography (SiO₂:gradient elution100:0 to 1:1 hex.: EtOAc) to afford the hydroxy compound (24 mg, 15%).

Step 3

Example 201 was prepared from the product of step 2 (24 mg) using aprocedure similar to that described in Scheme 11b step 2. The crudeproduct was purified via reverse phase flash chromatography (Cis;gradient elution 95:5:0.1 to 0:100:0.1 H₂O:MeCN:formic acid) to affordExample 201 (11 mg, 51%) as the formate salt.

LC/MS Conditions Method A:

Column: Gemini C-18, 50×4.6 mm, 5 micron, obtained from Phenomenex.

-   -   Mobile phase: A: 0.05% Trifluoroacetic acid in water        -   B: 0.05% Trifluoroacetic acid in acetonitrile    -   Gradient: 90:10 to 5:95 (A:B) over 5 min,    -   Flow rate: 1.0 mL/min    -   UV detection: 254 nm    -   ESI-MS: Electro Spray Ionization Liquid chromatography-mass        spectrometry (ESI-LC/MS) was performed on a PE SCIEX API-150EX,        single quadrupole mass spectrometer.

Method B:

Column: Waters SunFire C-18 4.6 mm×50 mm

-   -   Mobile phase: A: 0.05% Trifluoroacetic acid in water        -   B: 0.05% Trifluoroacetic acid in acetonitrile    -   Gradient: 90:10 (A:B) for 1 min, 90:10 to 0:100 (A:B) over 4        min, 0:100 (A:B) for 2 min.    -   Flow rate: 1.0 mL/min    -   UV detection: 254 nm    -   Mass spectrometer: Finnigan LCQ Duo electrospray.

Method C:

Column: Agilent Zorbax SB-C18 (3.0×50 mm) 1.8 uM

-   -   Mobile phase: A: 0.05% Trifluoroacetic acid in water        -   B: 0.05% Trifluoroacetic acid in acetonitrile    -   Gradient: 90:10 (A:B) for 0.3 min, 90:10 to 5:95 (A:B) over 5.1        min, 5:95 (A:B) for 1.2 min.    -   Flow rate: 1.0 mL/min    -   UV detection: 254 and 220 nm    -   Mass spectrometer: Agilent 6140 quadrupole.

Method D:

Column: Agilent Zorbax SB-C18 (3.0×50 mm) 1.8 uM

-   -   Mobile phase: A: 0.05% Trifluoroacetic acid in water        -   B: 0.05% Trifluoroacetic acid in acetonitrile    -   Gradient: 90:10 (A:B) for 0.3 min, 90:10 to 5:95 (A:B) over 1.2        min, 5:95 (A:B) for 1.2 min.    -   Flow rate: 1.0 mL/min    -   UV detection: 254 and 220 nm    -   Mass spectrometer: Agilent 6140 quadrupole.

Method E:

Column: Agilent Zorbax SB-C18 (3.0×50 mm) 1.8 uM

-   -   Mobile phase: A: 0.05% Trifluoroacetic acid in water        -   B: 0.05% Trifluoroacetic acid in acetonitrile

Gradient: 90:10 (A:B) for 0.1 min, 90:10 to 5:95 (A:B) over 1.0 min,5:95 (A:B) for 0.36 min.

-   -   Flow rate: 2.0 mL/min    -   UV detection: 254 and 220 nm    -   Mass spectrometer: Agilent 6140 quadrupole.

Method F:

Column: Agilent Zorbax SB-C18 (3.0×50 mm) 1.8 uM

-   -   Mobile phase: A: 0.05% Formic acid in water        -   B: 0.05% Formic acid in acetonitrile    -   Gradient: 90:10 to 5:95 (A:B) over 1.5 min, 5:95 (A:B) for 1.2        min.    -   Flow rate: 1.0 mL/min    -   UV detection: 254 and 220 nm    -   Mass spectrometer: Agilent 6140 quadrupole.

Assays

The protocol that was used to determine the recited values is describedas follows.

BACE1 HTRF FRET Assay Reagents Na⁺-Acetate pH 5.0 1% Brij-35 GlycerolDimethyl Sulfoxide (DMSO) Recombinant Human Soluble BACE1 CatalyticDomain (>95% Pure) APP Swedish Mutant Peptide Substrate(QSY7-APP^(awe)-Eu): QSY7-EISEVNLDAEFC-Europium-Amide

A homogeneous time-resolved FRET assay was used to determine IC₅₀ valuesfor inhibitors of the soluble human BACE1 catalytic domain. This assaymonitored the increase of 620 nm fluorescence that resulted from BACE1cleavage of an APPswedish APP^(swe) mutant peptide FRET substrate(QSY7-EISEVNLDAEFC-Europium-amide). This substrate contained anN-terminal QSY7 moiety that served as a quencher of the C-terminalEuropium fluorophore (620 nm Em). In the absence of enzyme activity, 620nm fluorescence was low in the assay and increased linearly over 3 hoursin the presence of uninhibited BACE1 enzyme. Inhibition of BACE1cleavage of the QSY7-APP^(swe)-Eu substrate by inhibitors was manifestedas a suppression of 620 nm fluorescence.

Varying concentrations of inhibitors at 3× the final desiredconcentration in a volume of 10 ul were preincubated with purified humanBACE1 catalytic domain (3 nM in 10 Ml) for 30 minutes at 30° C. inreaction buffer containing 20 mM Na-Acetate pH 5.0, 10% glycerol, 0.1%Brij-35 and 7.5% DSMO. Reactions were initiated by addition of 10 μl of600 nM QSY7-APP^(swe)-Eu substrate (200 nM final) to give a finalreaction volume of 30 μl in a 384 well Nunc HTRF plate. The reactionswere incubated at 30° C. for 1.5 hours. The 620 nm fluorescence was thenread on a Rubystar HTRF plate reader (BMG Labtechnologies) using a 50 μsdelay followed by a 400 millisecond acquisition time window. InhibitorIC₅₀ values were derived from non-linear regression analysis ofconcentration response curves. K_(i) values were then calculated fromIC₅₀ values using the Cheng-Prusoff equation using a previouslydetermined m value of 8 μM for the QSY7-APP^(swe)-Eu substrate at BACE1.

All of the example compounds of the invention were tested (except forExamples 8, 9, 10, 14b, 14c, 14d, 14e, and 14f) in this BACE-1 assay andexhibited K_(i) values of less than about 7.5 μM and greater than about0.5 nM in this assay. All of the example compounds except for examples19, 40×, 98, 101, and 189 exhibited K_(i) values of less than about 5 μMin this assay. Some of the example compounds exhibited K_(i) values ofless than about 4 μM in this assay; others less than about 3 μM in thisassay; others less than about 2 μM in this assay; others less than about1 μM in this assay; others less than about 500 nM in this assay; othersless than about 300 nM in this assay; others less than about 200 nM inthis assay; others less than about 100 nM in this assay; others lessthan about 50 nM in this assay; others less than about 10 nM in thisassay; others less than about 5 nM in this assay. The compound ofExample 45 exhibited a Ki value of about 26 nM in this assay. Thecompound of Example 47 exhibited a Ki value of about 6.5 nM in thisassay.

BACE-2 Assay

Inhibitor IC_(50s) at purified human autoBACE-2 were determined in atime-resolved endpoint proteolysis assay that measures hydrolysis of theQSY7-EISEVNLDAEFC-Eu-amide FRET peptide substrate (BACE-HTRF assay).BACE-mediated hydrolysis of this peptide results in an increase inrelative fluorescence (RFU) at 620 nm after excitation with 320 nmlight. Inhibitor compounds, prepared at 3× the desired finalconcentration in 1×BACE assay buffer (20 mM sodium acetate pH 5.0, 10%glycerol, 0.1% Brij-35) supplemented with 7.5% DMSO were pre-incubatedwith an equal volume of autoBACE-2 enzyme diluted in 1×BACE assay buffer(final enzyme concentration 1 nM) in black 384-well NUNC plates for 30minutes at 30° C. The assay was initiated by addition of an equal volumeof the QSY7-EISEVNLDAEFC-Eu-amide substrate (200 nM final concentration,K_(m)=8 LM for 4 μM for autoBACE-2) prepared in 1×BACE assay buffersupplemented with 7.5% DMSO and incubated for 90 minutes at 30° C. DMSOwas present at 5% final concentration in the assay. Following laserexcitation of sample wells at 320 nm, the fluorescence signal at 620 nmwas collected for 400 ms following a 50 μs delay on a RUBYstar HTRFplate reader (BMG Labtechnologies). Raw RFU data was normalized tomaximum (1.0 nM BACE/DMSO) and minimum (no enzyme/DMSO) RFU values.IC_(50s) were determined by nonlinear regression analysis (sigmoidaldose response, variable slope) of percent inhibition data with minimumand maximum values set to 0 and 100 percent respectively. SimilarIC_(50s) were obtained when using raw RFU data. The K_(i) values werecalculated from the IC₅₀ using the Cheng-Prusoff equation.

All of the example compounds of the invention were tested in this BACE-2assay except for the following examples: 2, 3, 4, 6, 7, 8, 9, 10, 11,12, 13, 14, 14b, 14c, 14d, 14e, 14f, 15, 16, 17, 19, 40a, 40b, 40ea, 40h, 40o, 40p, 40q, 40u, 40w, 40x, 40y, 40aa, 40au, 40ce, 40co, 40cp,40cy, 40dj, 40gy, 40gz, 40ha, 40hb, 40hc, 40ih, 41, 43, 45, 49, 60, 61,67, 68, 69, 70, 71, 73, 74, 75, 77, 85, 86, 88, 89, 90, 91, 96, 97, 98,99, 100, 101, 102, 103, 105, 108, 109, 109, 115, 116, 117, 122, 123,125, 130b, 137, 138, 143, 145, 161b, 176, 179, 182, 189, 192, 194, 195,199. Of the example compounds of the invention that were tested in thisBACE-2 assay, all exhibited K_(i) values of less than about 900 nM andgreater than about 0.04 nM in this assay. All of the example compoundsthat were tested in this assay, except for examples 40ex, 40do, 160,161a, 164, and 197 exhibited K_(i) values of less than about 500 nM inthis assay. Some of the example compounds exhibited K_(i) values of lessthan about 200 nM in this assay; others less than about 100 nM in thisassay; others less than about 50 nM in this assay; others less thanabout 25 nM in this assay; others less than about 10 nM in this assay;others less than about 5 nM in this assay; others less than about 1 nMin this assay; others less than about 0.5 nM in this assay. The compoundof Example 47 exhibited a Ki value of about 1 nM in this assay.

The novel iminothiadiazine dioxide compounds of the invention havesurprisingly been found to exhibit properties which are expected torender them advantageous as BACE inhibitors and/or for the variousmethods of used herein.

Cortical Aβ₄₀

The iminothiadiazine dioxide compounds of the invention have been found,surprisingly and advantageously, to exhibit improved efficacy inlowering Aβ₄₀ production in the cerebral cortex than theiriminopyrimidone analogs. The following procedures were used. Results areshown in the table below.

Rat Tissue Collection

Male CD rats (˜100 g; Crl:CD(SD); Charles River Laboratories, Kingston,N.Y.) were group housed and acclimated to the vivarium for 5-7 daysprior to use in a study. Compounds were formulated in 20%hydroxypropyl-β-cyclodextrin and administered orally with a dosingvolume of 5 ml/kg for rats. Three h after drug administration, rats wereeuthanized with excess CO₂. The brain was removed from the skull andimmediately frozen on dry ice. All tissues were stored at −70° C. untilAβ quantification.

Determination of Aβ₄₀ Levels in Rat Cortex by ELISA

The measurement of endogenous rat Aβ1-40 (Aβ40) in cortex relied on the585 antibody (Ab585, BioSource), catalogue no. NONO585), whichspecifically recognizes the N-terminal sequence of rodent Aβ40, and themonoclonal antibody, G2-10, which specifically recognizes the freeC-terminus of Aβ340. Ab585 was labeled with biotin (b-Ab585) by firstdialyzing the antibody sample extensively versus PBS (pH 7.8) to removeimpurities, followed by dilution to between 1 and 2 mg/mL proteinconcentration. EZ-Link Sulfo-NHS-LC-Biotin (Pierce) was dissolved in PBS(pH 7.8) at a concentration of 1 mg/mL immediately prior to use. Ab585was labeled with EZ-Link Sulfo-NHS-LC-biotin using a 10:1biotin:antibody ratio by incubation at room temperature for 1 hour. Thelabeling reaction was quenched by addition of 1.0 M glycine to a finalconcentration of 0.1 M followed by 10 minute incubation at roomtemperature. Glycine was removed by extensive dialysis versus PBS.

The use of the Luminex based immunoassay for measurement of rat corticalAβ40 required that the G2-10 antibody be labeled with Bio-Plex COOH Bead25 (Bio-Rad laboratories catalogue no. 171506025). The antibody wascoupled to the beads using the Bio-Plex Amine Coupling Kit (Bio-Rad) asper the manufacturer's recommendations.

Rat cortex Aβ340 levels were measured from guanidine HCl extracts ofindividual rat cortices using a Luminex-based immunodetection assay. Ratbrains were thawed briefly at 37° C. and both mid- and hindbrain regionswere removed. The remaining material, consisting primarily of cortex(˜800 mg) was carried through the guanidine extraction procedure.Cortices were added to a 2 ml BioPur tube (Eppendorf) along with a 6.35mm chrome-coated steel ball and 1.0 ml of sucrose homogenization buffer(20 mM HEPES [pH 7.5], 50 mM KCl, 50 mM sucrose, 2 mM EDTA, 2 mM EGTAsupplemented with complete protease inhibitors [Roche, EDTA-free]).Samples were then homogenized by agitation for 1.5 min at 30 cylces/secin a MM300 tissue mixer (Retsch®). The resulting cortical homogenate wasextracted with guanidine-HCl by mixing 67 μl of homogenate with 133 μlof 5 M Guanidine HCl, 50 mM Tris HC (pH 8.0). To maximize the efficiencyof Aβ extraction, samples were vortexed and then sonicated for 2 minutesin an ice bath using an Ultrasonics XL cup horn sonicator at a powersetting of 8 (Heat Systems, Inc.). Insoluble material was removed byultracentrifugation using a using a TLA-55 rotor in a TL-100 benchtopcentrifuge (Beckman) at 100,000×g for 30 minutes. The resultingsupernatant was then either diluted 1:10 in 5 M guanidine HCl, 0.05 MTris HCl (pH 8.0) for protein analysis (BCA protein assay, PierceBiochemicals) or assayed neat for Aβ340 levels. The Luminex rodent Aβ40assay was performed as follows. First, 96 well filter binding plates(Millipore, catalogue # MSBVN12) were wetted with 100 μl of 1×LAβ40buffer (0.05 M HEPES [pH 7.5], 0.2% BSA, 0.2% Tween-20, 0.15 M NaCl) byvacuum filtration on a Millipore 96-well manifold. The plate bottom wassealed and 100 μl of 1×LAβ40 buffer was added to each well followed byaddition of 50 μl each of G2-10:COOH beads (1000 beads/well) and 50 μlb-Ab585 at 0.5 μg/ml in 1×LAβ40 buffer. Guanidine HCl was added tosynthetic rodent Aβ40 standards in order to control for the effect ofguanidine in brain extracts on the assay performance. Ten microliters ofcortical extract, rodent Aβ40 standards or cortical extract from amyloidprecursor protein knockout mice (to define background immunoreactivity)was added to each well. Plates were covered and incubated overnight at4° C. Following the incubation, wells were cleared by vacuum and washedtwice with 100 μl of 1×LA40 buffer on a Millipore manifold.Phycoerythrin-conjugated streptavidin (PE-strepavidin, BioRad) fordetection of bound b-Ab585 was diluted 100-fold in 1×LAβ40 buffer and 50μl was added to each well and incubated for 1 hour at room temperaturewith shaking. Unbound PE-streptavidin was removed by three 100 μl washeswith cytokine assay buffer (BioRad). Washed beads were resuspended in125 μl of cytokine assay buffer by shaking on a microplate shaker.Plates were read on a BioPlex suspension array system (BioRad) withtarget region beads set to 40 beads/region and the upper end of the DDgate set to 10,000. Raw fluorescence data was analyzed using nonlinearregression analysis and absolute Aβ40 levels were extrapolated from thestandard curve using GraphPad Prism 4.0.2. Absolute amounts of Aβ₁₋₄₀are expressed as picograms per micrograms protein. Percent change valuesfor each compound were calculated by normalization of the averageabsolute cortical Aβ1-40 level in each compound treated cohort to theaverage absolute cortical Aβ1-40 levels in the vehicle cohort.Comparative results are shown in the table below. “NT” means not tested.

Change in Cortical Aβ₄₀ in Rats 3 h After a 10 mg/kg Oral Dose ofCompound Iminothiadiazine Dioxide Iminopyrimidinone BACE-1 Change ChangeKi (nM) in rat in rat Ex. BACE-2 cortex cortex # Structure Ki (nM) Aβ₄₀Structure Aβ₄₀  34

0.949 0.22  −51%

−19%  26

1.261 2.46  −33%

   0%  25

1.753 0.37  −49%

−11%  36

10    4.85  −25%

NT  40di

1.05  2.15  −38%

 +5%  35

3.0  0.45  NT

NT 173

4.88  0.47  −27%

 −3%  45

25.6   NT NT

 −5%  46

46    8.23  NT

NT  52

2.387 0.37  −53%

−54%  40ai

1.64  1.99  −51%

Caco-2 Bi-Directional Permeability

It has been found that compounds of the invention exhibit unexpectedlyreduced susceptibility to efflux by P-glycoprotcin (P-gp) versuscompounds having an iminopyrimidinone moiety that are otherwisestructurally identical. β-gp is found, among other locations, at theblood-brain barrier, and reduced susceptibility to efflux by thisprotein is a desirable characteristic of centrally acting compounds (A.Schinkel Advanced Drug Delivery Reviews 1999, 36, 179-194). Thefollowing procedures were used. Results are shown in the table below.

Caco-2 Bi-directional Permeability

The bi-directional permeability with efflux potential of selectedcompounds of the invention vs. otherwise structurally identicaliminopyrimidinones (collectively referred to as test compounds, shown inthe table below) were assessed using Caco-2 cell line. The Caco-2 cellswere maintained in DMEM (Dulbecco's Modified Eagle Medium) containing10% fetal bovine serum, 1% non-essential amino acids, 2 mM L-glutamine,and 1% penicillin-streptomycin in an incubator at ˜37° C. in anatmosphere of 5% CO₂ and about 90% relative humidity. The cell culturemedium was changed three times weekly. Caco-2 cell monolayers were grownon polyethylene terephthalate filters using 24-well BD Falcon™ CellCulture Insert Plates (0.33 cm² insert area, 1 μm pore size; BDBioSciences, Bedford, Mass.). The culture medium of the plate waschanged every other day until used for the transport experiment (21-28days post seeding).

The transport buffer (TM) was Hank's balanced salt solution (HBSS) with10 mM HEPES and 25 mM glucose (pH 7.4) for dosing and TM with 4% bovineserum albumin for receiver (pH 7.4). The bi-directional permeability ofthe test compounds were tested at concentrations of 1, 10 and 100 μM wasmeasured in triplicate with 2-hr incubation. The cell monolayerintegrity was monitored with pre- and post-experimental trans-epithelialelectrical resistance and post-experimental Lucifer Yellow (LY)permeability with 1 hr incubation. Test article samples were analyzedusing LC-MS/MS and the concentration of LY was measured using a PerkinElmer HTS 7000 Plus Bio Assay Reader (Waltham, Mass.) with an excitationand emission wavelength of 485 nm and 538 nm, respectively.

The apparent permeability, recovery and efflux ratio values werecalculated using the following equations:

${P_{app}\left( \text{nm/s} \right)} = {\frac{{\text{M/}}{t}}{S*C_{0}} = {\frac{{{C_{R}/}}{t}*V_{R}}{S*C_{0}}*10^{7}}}$${{Efflux}\mspace{14mu} {Ratio}} = \frac{P_{{app}_{—}{BLtoAP}}}{P_{{app}_{—}{APtoBL}}}$${{Total}\mspace{14mu} {Recovery}\mspace{14mu} (\%)} = {{\frac{C_{D,{final}}}{C_{0}} \times 100} + {\frac{{Receiver}\mspace{14mu} {Accumulated}\mspace{14mu} {Amount}}{C_{0}*V_{D}} \times 100}}$

where,

-   -   dC_(R)/dt: The slope of the accumulative concentration in the        receiver compartment versus time incubation (μM·s⁻¹)    -   C_(0hr): Donor concentration (μM) immediately after dosing    -   C_(D, final): Donor concentration (μM) at the end of incubation    -   S: Membrane surface area (cm²)    -   V_(D): Volume of donor compartment (mL)    -   V_(R): Volume of receiver compartment (mL)    -   P_(app) _(_) _(BLtoAP): Permeability from basolateral (BL) to        apical (AP) transport    -   P_(app) _(_) _(APtoBL): Permeability from AP to BL transport

Evaluation of P-Gp Efflux Inhibition Using Caco-2 Bi-DirectionalPermeability Assay

A preliminary study to assess the compounds in the table below aspotential β-gp substrates were performed using the Caco-2 bi-directionaltransport assay. Digoxin was used as a probe β-gp substrate. The³H-digoxin dosing solution was prepared by diluting a digoxin DMSO stockwith TM and/or the inhibitor solutions and titrating with ³H-digoxin(final digoxin concentration was 5 μM with 0.5 μCi/mL radioactivity).Two concentrations of test compounds (5 and 50 μM) were prepared bydiluting a DMSO stock solution with TM (pH 7.4). The Caco-2bi-directional permeability of ³H-digoxin with or without test compoundas inhibitor was measured as described in the Caco-2 bi-directionalpermeability section. The total radioactivity for each sample wascounted using a Packard 2250CA Tri-Carb Liquid Scintillation Analyzer.

The percentage of digoxin efflux inhibition was calculated using thefollowing equation:

${\%_{—}{Inhibition}} = {\left( {1 - \frac{P_{{app}_{—}{BLtoAP}}^{inhibitor} - P_{{app}_{—}{APtoBL}}^{inhibitor}}{P_{{app}_{—}{BLtoAP}} - P_{{app}_{—}{APtoBL}}}} \right)*100}$

where,

-   -   P_(app) _(_) _(BLtoAP): Digoxin permeability from BL to AP        transport    -   P_(app) _(_) _(APtoBL): Digoxin permeability from AP to BL        transport    -   P_(app) _(_) _(BLtoAP) ^(inhibitor): Digoxin permeability with        inhibitor from BL to AP transport:        -   Digoxin permeability with inhibitor from AP to BL transport

Permeability (AP→BL) and efflux ratio in Caco-2 cells (AP = apical, BL =basolateral) Iminothiadiazine Dioxide Iminopyrimidinone Caco-2 Caco-2Caco-2 Caco-2 Ex. AP→BL Efflux AP→BL Efflux # Structure (nm/s) ratioCmpd. # (nm/s) ratio  34

118 3.1

 0 NA  26

 89 2.9

 17 11.3  25

128 2.4

 22 10.6  36

 54 3.3

 11 12.9  40di

136 2.0

 65  3.2  35

151 2.1

 0 NA 173

126 2.2

 25  6.1  45

226 1.4

174  2.6  46

189 1.9

136  2.6  52

278 1.6

153  2.4  40ai

133 1.8 NA

Solution Stability

The iminothiadiazine dioxide compounds of the invention have been found,surprisingly and advantageously, to exhibit improved solution stability(e.g., by resistance to hydrolysis) compared with structurally similariminopyrimidinones. The following comparative procedures were used.Results are reported as Examples A and B below.

A 1.05 mg/mL stock solution (5 mL) of Ex. 45 in MeOH was prepared. Fromthe stock solution was taken out 1.25 mL and diluted to 25 mL with theaddition of 23.75 mL of 10 mM phosphate buffer (pH 7.4)/MeOH (70/30v/v). This new solution was split into three. One solution was incubatedat 4° C., another incubated at 25° C. and the third incubated at 40° C.Each solution was analyzed by LC/MS after day 1, day 2 and day 6 andcompared to a standard calibration curve for Ex. 45.

Example A Stability Studies Comparing Example 45 with Compound Z

In the following study, the solution stability of the compound ofExample 45 was measured and compared to that of Compound Z. The compoundof Example 45 is an iminothiadiazine dioxide compound of the invention.Compound Z is the corresponding iminopyrimidinone compound. Thestructures of the compound of Example 45 and of Compound Z are shownbelow. Studies were performed in aqueous pH 7.4 buffer containingmethanol at 4° C., 25° C. and 40° C. At 4° C., the compound of Example45 showed 0.93% degredation after 6 days while Compound Z showed 18.3%degredation after 1 day. At 25° C., the compound of Example 45 showed7.4% degredation after 6 days while Compound Z showed 53.87%degredation. At 40° C., the compound of Example 45 showed 30.71%degredation after 6 days while Compound Z showed 79.93% degredationafter 1 day.

Solution Stability for Ex. 45 in pH 7.4 Condition  4° C. Batch Number 7Time, days Initial 1 2 6 Assay (Area %) 99.82 99.69 99.04 98.89Condition 25° C. Assay (Area %) 99.82 98.45 96.07 92.43 Condition 40° C.Assay (Area %) 99.82 96.32 89.70 69.11 — a: Results by areanormalization ND = Not Detected. (—) stands for >20% degradationSolution Stability for Compound Z in pH 7.4 Condition  4° C. BatchNumber 7 Time, days Initial 1 2 6 Assay (Area %) 88.15 69.84 — — —Condition 25° C. Assay (Area %) 88.15 34.28 — — — Condition 40° C. Assay(Area %) 88.15  8.22 — — — a: Approximate RRT for related compounds.Results by area normalization ND = Not Detected. (—) stands for >20%degradation

Stock solutions of the tested compounds were prepared by dissolvingabout 3 mg of each compound in 3 mL of acetonitrile. Standards for testcompounds were prepared by diluting 1 mL of the stock solution with anadditional 4 mL of acetonitrile. These standards were stored at 4° C.Samples were prepared by diluting 1 mL of the stock solution with 4 mLof 50 mM pH 7.4 phosphate buffer. These samples were stored at 25° C. inthe absence of light. Standards and samples were analyzed by LC/MSinitially and at day 1, day 4, and day 6.

HPLC conditions:

Mobile phase A: 10 mM pH 5 ammonium acetate buffer:methanol (90:10)

Mobile phase B: 10 mM pH 5 ammonium acetate buffer:methanol (10:90)

Column: Zorbax SB-Phenyl 4.6×50 mm, 1.8 μm

Column temperature: 40° C.

Flow: 0.8 mL/min.

Gradient:

Time (min.) % B 0 40 9 100 11 100

Detectors: UV at 220 nm and 236 nm

MS, ES ionization, positive mode, for identification only at final timepoint.

The terms reported in the tables below have the following meanings:

Area % is the integration of peak from HPLC as reported by WatersEmpower II software.

RRT is the relative retention time of new product compared to thestandard of the test compound.

Formula for RRT is:

$\frac{{Retention}\mspace{14mu} {time}\mspace{14mu} {of}\mspace{14mu} {new}\mspace{14mu} {product}}{{Retention}\mspace{14mu} {time}\mspace{14mu} {of}\mspace{20mu} {standard}}$

M+1 is the mass observed including protonation (+1 mass unit).

ND stands for no peak detected by the UV detector.

* stands for no ion detected by the mass spectrometer.

Example B Stability Studies Comparing Example 47 with Compound Y

In the following study, the solution stability of the compound ofExample 47 was measured and compared to that of Compound Y. The compoundof Example 47 is an iminothiadiazine dioxide compound of the invention.Compound Y is the corresponding iminopyrimidinone compound. Thestructures of the compound of Example 47 and of Compound Y are shownbelow. Studies were performed in pH 7.4 buffer at 25° C. Under theseconditions, the compound of Example 47 showed 0% hydrolysis productafter 6 days while Compound Z showed 12.45% hydrolysis product.

Example 20 Free Base MW=374.09

Area Area Area %, %, %, Peak Area %, Day Day Day Description RRT M + 1Initial 1 4 6 Standard Example 47 1.00 375.10 98.53 98.55 98.52 98.52Unknown 1.49 * 1.47 1.45 1.48 1.48 Sample at Example 47 1.00 375.1098.55 98.56 98.53 98.53 pH 7.4 Unknown 1.49 * 1.45 1.44 1.47 1.47

Compound Y: Free Base MW=338.12

Peak Area %, Area %, Area %, Area %, Description RRT M + 1 Initial Day 1Day 4 Day 6 Standard Compound Y 1.00 339.15 100.0 100.0 100.0 100.0Sample at Compound Y 1.00 339.10 99.36 96.89 93.02 87.55 pH 7.4Hydrolysis product 0.76 357.10 0.64 3.11 6.98 12.45

While the present invention has been described in view of the specificembodiments set forth above, many alternatives, modifications and othervariations thereof will be apparent to those of ordinary skill in theart. All such alternatives, modifications and variations are intended tofall within the spirit and scope of the present invention.

1-19. (canceled)
 20. A method of treating Alzheimer's disease in a humanin need thereof comprising administering to the human a therapeuticallyeffective amount of a compound, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or said tautomer, saidcompound selected from the group consisting of:


21. A method of treating Alzheimer's disease in a human in need thereofcomprising administering to the human a therapeutically effective amountof a compound having a structure:

or a tautomer thereof, or a pharmaceutically acceptable salt of saidcompound or said tautomer.
 22. The method of claim 21, wherein saidcompound is a compound having a structure:

or a tautomer thereof.
 23. The method of claim 22, wherein said compoundis a pharmaceutically salt of a compound having a structure:

or a pharmaceutically acceptable salt of a tautomer thereof, whereinsaid pharmaceutically acceptable salt is selected from the groupconsisting of acetate, ascorbate, benzoate, benzenesulfonate, bisulfate,borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate,hydrochloride, hydrobromide, hydroiodide, lactate, maleate,methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate,propionate, salicylate, succinate, sulfate, tartarate, thiocyanate, andtoluenesulfonate.
 24. The method of claim 23, wherein saidpharmaceutically acceptable salt is a hydrochloride salt.
 25. The methodof claim 23, wherein said pharmaceutically acceptable salt is atoluenesulfonate salt.
 26. A method of treating mild cognitiveimpairment in a human in need thereof comprising administering to thehuman a therapeutically effective amount of a compound, or a tautomerthereof, or a pharmaceutically acceptable salt of said compound or saidtautomer, said compound selected from the group consisting of:


27. A method of treating mild cognitive impairment in a human in needthereof comprising administering to the human a therapeuticallyeffective amount of a compound having a structure:

or a tautomer thereof, or a pharmaceutically acceptable salt of saidcompound or said tautomer.
 28. The method of claim 27, wherein saidcompound is a compound having a structure:

or a tautomer thereof.
 29. The method of claim 28, wherein said compoundis a pharmaceutically salt of a compound having a structure:

or a pharmaceutically acceptable salt of a tautomer thereof, whereinsaid pharmaceutically acceptable salt is selected from the groupconsisting of acetate, ascorbate, benzoate, benzenesulfonate, bisulfate,borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate,hydrochloride, hydrobromide, hydroiodide, lactate, maleate,methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate,propionate, salicylate, succinate, sulfate, tartarate, thiocyanate, andtoluenesulfonate.
 30. The method of claim 29, wherein saidpharmaceutically acceptable salt is a hydrochloride salt.
 31. The methodof claim 29, wherein said pharmaceutically acceptable salt is atoluenesulfonate salt.
 32. A method of lowering the production of Aβ₄₀in the cerebral cortex of a human in need thereof comprisingadministering to the human a therapeutically effective amount of acompound, or a tautomer thereof, or a pharmaceutically acceptable saltof said compound or said tautomer, said compound selected from the groupconsisting of:


33. A method of lowering the production of Aβ₄₀ in the cerebral cortexof a human in need thereof comprising administering to the human atherapeutically effective amount of a compound, having a structure:

or a tautomer thereof, or a pharmaceutically acceptable salt of saidcompound or said tautomer.
 34. The method of claim 33, wherein saidcompound is a compound having a structure:

or a tautomer thereof.
 35. The method of claim 33, wherein said compoundis a pharmaceutically salt of a compound having a structure:

or a pharmaceutically acceptable salt of a tautomer thereof, whereinsaid pharmaceutically acceptable salt is selected from the groupconsisting of acetate, ascorbate, benzoate, benzenesulfonate, bisulfate,borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate,hydrochloride, hydrobromide, hydroiodide, lactate, maleate,methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate,propionate, salicylate, succinate, sulfate, tartarate, thiocyanate, andtoluenesulfonate.
 36. The method of claim 35, wherein saidpharmaceutically acceptable salt is a hydrochloride salt.
 37. The methodof claim 35, wherein said pharmaceutically acceptable salt is atoluenesulfonate salt.
 38. A method of inhibiting the formation of Aβpeptides in a human in need thereof, which method comprisesadministering to the human a therapeutically effective amount of acompound, or a tautomer thereof, or a pharmaceutically acceptable saltof said compound or said tautomer, wherein said compound is selectedfrom the group consisting of:


39. A method of inhibiting the formation of Aβ peptides in a human inneed thereof comprising administering to the human a therapeuticallyeffective amount of a compound having a structure:

or a tautomer thereof, or a pharmaceutically acceptable salt of saidcompound or said tautomer.
 40. The method of claim 39, wherein saidcompound is a compound having a structure:

or a tautomer thereof.
 41. The method of claim 40, wherein said compoundis a pharmaceutically salt of a compound having a structure:

or a pharmaceutically acceptable salt of a tautomer thereof, whereinsaid pharmaceutically acceptable salt is selected from the groupconsisting of acetate, ascorbate, benzoate, benzenesulfonate, bisulfate,borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate,hydrochloride, hydrobromide, hydroiodide, lactate, maleate,methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate,propionate, salicylate, succinate, sulfate, tartarate, thiocyanate, andtoluenesulfonate.
 42. The method of claim 41, wherein saidpharmaceutically acceptable salt is a hydrochloride salt.
 43. The methodof claim 41, wherein said pharmaceutically acceptable salt is atoluenesulfonate salt.